Amantadine compositions and methods of use

ABSTRACT

Methods of nighttime administration of amantadine to reduce sleep disturbances in patient undergoing treatment with amantadine are described, as well as compositions of extended release amantadine that are suitable for nighttime administration.

CROSS-REFERENCE

This application is a continuation of U.S. patent application Ser. No.14/863,035, filed Sep. 23, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/523,535, filed Oct. 24, 2014, now abandoned,which is a continuation of U.S. patent application Ser. No. 14/267,597,filed May 1, 2014, now abandoned, which is a continuation of U.S. patentapplication Ser. No. 12/959,321, filed Dec. 2, 2010, now U.S. Pat. No.8,741,343, which claims benefit of U.S. Provisional Application No.61/266,053, filed Dec. 2, 2009, all of which applications areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The field of the invention is extended release compositions ofamantadine and uses thereof.

Amantadine is indicated for various conditions that can be treated byNMDA receptor antagonists including the treatment of idiopathicParkinson's disease (Parlysis Agitans), postencephalitic Parkinsonism,and symptomatic Parkinsonism which may follow injury to the nervoussystem by carbon monoxide intoxication. Amantadine also has activity asa viral M2 channel inhibitor and is used for the prophylaxis andtreatment of infection of viral diseases, especially influenza A virus.

Currently marketed forms of amantadine are immediate releaseformulations that are typically administered two or more times a day.Amantadine's use is limited by dose related CNS side effects includingdizziness, confusion, hallucinations, insomnia and nightmares (Gracies JM, Olanow C W; Current and Experimental Therapeutics of Parkinson'sDisease; Neuropsychopharmacology: the Fifth Generation of Progress, p.1802; American College of Neuropsychopharmacology 2002), which can beparticularly exacerbated when amantadine is administered at night.

It is known that immediate release amantadine can act as a stimulant,causing insomnia and sleep disturbance. Therefore, the last dose istypically administered no later than 4 pm in order to minimize theseside effects. Such dosing of amantadine results in peak plasmaamantadine concentrations occurring in the evening or night, and verylow plasma concentrations in the morning.

Extended release forms of amantadine have been described in the art.U.S. Pat. No. 5,358,721, to Guittard et al., and U.S. Pat. No.6,217,905, to Edgren et al., each disclose an oral osmotic dosage formcomprising an antiviral or anti-Parkinson's drug, respectively, where ineach case amantadine is listed as a possible drug to be utilized in thedosage form. U.S. Pat. No. 6,194,000, to Smith et al., disclosesanalgesic immediate and controlled release pharmaceutical compositionsutilizing NMDA receptor antagonists, such as amantadine, as the activeagent. U.S. Patent Appl. Publication Nos. US 2006/0252788, US2006/0189694, US 2006/0142398, and US 2008/0227743, all to Went et al.,each disclose the administration of an NMDA receptor antagonist, such asamantadine, optionally in controlled release form.

SUMMARY OF THE INVENTION

The inventors have identified a need in the art for improvedformulations of amantadine that result in a patient having higher plasmaconcentrations of amantadine upon waking in the morning withoutadversely affecting sleep. Further, the inventors have identified a needin the art for a method of administering amantadine in the lateafternoon or evening, e.g. after 4 pm, which reduces side effects ofinsomnia and sleep disturbance and provides effective plasmaconcentrations of amantadine upon waking.

Therefore, there exists a need in the art for improved methods ofamantadine therapy which can be administered to a patient shortly beforethey wish to sleep (e.g., at bedtime) without causing insomnia or sleepdisturbance. In addition, there is a need for an amantadine therapywhich can be taken by the patient before they go to sleep and thenprovides a suitable plasma concentration of amantadine when they wakeup, e.g. in the morning, after a full night's sleep.

In addition, many Parkinson's disease patients have difficultyswallowing and are on multiple medications. Hence there is a need foramantadine therapy that delivers a therapeutically effective dose of thedrug, can be administered once daily and is in an oral dosage form thatis small in size and does not unduly increase the pill burden.

One aspect of the invention is a method of administering amantadine to apatient in need thereof, said method comprising orally administering anextended release (ER) composition comprising amantadine, or apharmaceutically acceptable salt thereof, less than three hours beforebedtime (i.e. the time at which the subject wishes to go to sleep forthe night). This aspect also includes the use of such compositions andthe use of amantadine for the manufacture of a medicament as describedbelow. Alternatively, the composition is administered less than about 4hours before bedtime.

In a second aspect, the invention provides a method of reducing sleepdisturbance in a human subject undergoing treatment with amantadine,said method comprising administering an extended release (ER)composition comprising amantadine, or a pharmaceutically acceptable saltthereof, less than about three hours before bedtime (i.e. the time atwhich the subject wishes to go to sleep for the night). This aspect alsoincludes the use of such compositions and the use of amantadine for themanufacture of a medicament as described below. Alternatively, thecomposition is administered less than about 4 hours before bedtime.

In a third aspect, the invention provides a method of treating levodopainduced dyskinesia, or fatigue, or dementia, or any other symptom ofParkinson's disease, said method comprising administering an extendedrelease (ER) composition comprising amantadine, or a pharmaceuticallyacceptable salt thereof, less than about three hours before bedtime(i.e. the time at which the subject wishes to go to sleep for thenight). This aspect also includes the use of such compositions and theuse of amantadine for the manufacture of a medicament as describedbelow.

In a fourth aspect, the invention provides a method of treating braininjury, brain trauma, dementia, Alzheimer's disease, stroke,Huntington's disease, ALS, Multiple Sclerosis, neurodegenerativediseases, dementias, cerebrovascular conditions, movement disorders,cranial nerve disorders, neuropsychiatric disorders, said methodcomprising administering an extended release (ER) composition comprisingamantadine, or a pharmaceutically acceptable salt thereof, less thanabout three hours before bedtime (i.e. the time at which the subjectwishes to go to sleep for the night). This aspect also includes the useof such compositions and the use of amantadine for the manufacture of amedicament as described below.

In one embodiment of any of the above aspects, administration occursless than two and a half, less than two, less than one and a half, lessthan one or less than half hour before bedtime (i.e. the time at whichthe subject wishes to go to sleep for the night).

In one embodiment of any of the above aspects the patient has beendiagnosed with Parkinson's disease.

In one embodiment of any of the above aspects, the composition isadministered once daily. In another aspect, the daily dose exceeds 200mg, and is given in 1, 2 or 3 capsules of size 0, 1 or 2.

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in levodopa induced dyskinesia (LID). In a specificembodiment, administration of the composition results in about 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80%reduction in levodopa induced dyskinesia. In further embodiments, thereduction in levodopa induced dyskinesia is measured on a numeric scalethat is used by the FDA to evaluate effectiveness of drugs indicated toreduce LID. In further specific embodiments, the scale used in measuringthe reduction in LID could be UDysRS, UPDRS Part IV (subscores 32, 33),Dyskinesia Rating Scale (DRS), Abnormal Involuntary Movement Scale(AIMS), or other scales developed for this purpose.

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in Parkinson's disease fatigue. In a specific embodiment,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% reduction in Parkinson'sdisease fatigue. In further specific embodiments, the reduction infatigue is measured on a numeric scale that is used by the FDA toevaluate effectiveness of drugs indicated to reduce fatigue. In furtherspecific embodiments, the scale used in measuring the reduction infatigue could be the Fatigue Severity Scale (FSS).

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in Parkinson's disease symptoms. In a specific embodiment,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, or 40% reduction in Parkinson's symptoms. In furtherspecific embodiments, the reduction in Parkinson's symptoms is measuredon a numeric scale that is used by the FDA to evaluate effectiveness ofdrugs indicated to reduce Parkinson's symptoms. In further specificembodiments, the scale used in measuring the reduction in Parkinson'ssymptoms could be the Unified Parkinson's Disease Rating Scale (UPDRS).

In one embodiment of any of the above aspects, the composition is addedto food, and in a more specific embodiment to a small amount of softfood (e.g. applesauce or chocolate pudding), prior to administration.Addition to food may involve a capsule being opened and the contentssprinkled over the patient's food. This is advantageous if the patientis unable or unwilling to swallow the composition.

In one embodiment of any of the above aspects, there is no increase inplasma concentration of amantadine for at least one hour after theadministration at steady state plasma concentrations.

In one embodiment of any of the above aspects, there is no increase inthe plasma concentration of amantadine for at least two hours after theadministration at steady state plasma concentrations.

In one embodiment of any of the above aspects, the administration of thecomposition to a human subject at steady state amantadine plasmaconcentrations increases the amantadine plasma concentration by lessthan 5%, 10%, 15%, 20% or 25% at 1, 2, 2.5 or 3 hours following suchadministration. For example, administration of the composition to ahuman subject at steady state amantadine plasma concentrations increasesthe amantadine plasma concentration by less than 5% at 1, 2, 2.5 or 3hours following such administration; or by less than 10% at 1, 2, 2.5 or3 hours following such administration; or by less than 15% at 1, 2, 2.5or 3 hours following such administration; or by less than 20% at 1, 2,2.5 or 3 hours following such administration; or by less than 25% at 1,2, 2.5 or 3 hours following such administration.

In one embodiment of any of the above aspects the amantadine has asingle dose Tmax of 9 to 15 hours. In a more specific embodiment, theamantadine has a single dose Tmax of 10 to 14 hours afteradministration. In another more specific embodiment, the amantadine hasa single dose Tmax of 11 to 13 hours after administration.

In one embodiment of any of the above aspects the amantadine has asteady state Tmax of 7 to 13 hours. In a more specific embodiment, theamantadine has a steady state Tmax of 8 to 12 hours afteradministration. In another more specific embodiment, the amantadine hasa steady state Tmax of 9 to 11 hours after administration.

In one embodiment of any of the above aspects peak plasma concentrationof amantadine is achieved between 6 and 16 hours after administration ofa single dose of the composition. In a more specific embodiment, peakamantadine plasma concentration is achieved 8 to 14 hours afteradministration of a single dose of the composition. In another morespecific embodiment, peak amantadine plasma concentration is achieved 10to 12 hours after administration of a single dose of the composition. Inadditional specific embodiments, peak amantadine plasma concentration isachieved between 6, 7, 8, 9, 10, 11 or 12 hours to about 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours afteradministration of a single dose of the composition.

In one embodiment of any of the above aspects, a once daily oraladministration of the composition to a human subject provides a steadystate plasma concentration profile characterized by a concentrationincrease of amantadine of less than 25% at three hours after theadministration. In a more specific embodiment, the steady state plasmaconcentration profile is characterized by a concentration increase ofamantadine of less than 25% at four hours after the administration.

In one embodiment of any of the above aspects, the composition isadministered once a day and the ratio of Cmax to Cmin at steady state is1.5 to 2.0, or, more specifically, 1.7 to 1.9, or, more specifically,about 1.8.

In one embodiment of any of the above aspects, the steady state plasmaconcentration profile following multiple administrations to a humansubject of the composition at bedtime is characterized by an averageplasma concentration during the day (“C-ave-day”, defined as the averageday time amantadine plasma concentration as measured in a human PKstudy) that is 1.1 to 2.0 times the average plasma concentration duringthe night (“C-ave-night”, defined as the average night time amantadineplasma concentration as measured in a human PK study). In more specificembodiments the C-ave-day is the average amantadine plasma concentrationas measured between the hours of 5 am, 6 am, 7 am, 8 am or 9 am to thehours of 4 pm, 5 pm, 6 pm, 7 pm or 8 pm; for example, between the hoursof 6 am and 4 pm, between the hours of 7 am and 6 pm, or between thehours of 7 am and 5 pm. The C-ave-night is the average amantadine plasmaconcentration as measured between the hours of 4 pm, 5 pm, 6 pm, 7 pm, 8pm, 9 pm, 10 pm or 11 pm to the hours of 5 am, 6 am, 7 am, 8 am or 9 am;for example, between the hours of 10 pm and 6 am, between the hours of 7pm and 6 am, or between the hours of 8 pm and 6 am.

In one embodiment of any of the above aspects, the steady state plasmaconcentration profile following multiple administrations to a humansubject of the composition at bedtime is characterized by an averageplasma concentration during the morning (“C-ave-morning”, defined as theaverage amantadine plasma concentration as measured in a human PK studyduring the morning hours) that is 1.1 to 2.0 times the average plasmaconcentration during the night. In one embodiment the C-ave-morning isthe average amantadine plasma concentration as measured between thehours of 5 am, 6 am, 7 am, 8 am or 9 am to the hours of 11 am, 11:30 am,12 pm, 12:30 pm or 1:00 pm; for example, between the hours of 5 am and11 am, or between the hours of 7 am and 12 pm. More preferably, theratio of C-ave-morning/C-ave-night at steady state is 1.2 to 1.6.

In one embodiment of any of the above aspects, the steady state plasmaconcentration profile following daily administration of the compositionis characterized by an average plasma concentration during the period 8hours to 12 hours after administration (“C-ave-8-12 hrs”) that is 1.1 to2.0 times the average plasma concentration during the first 8 hoursafter administration (“C-ave-0-8 hrs”). More preferably, the ratio ofC-ave-8-12 hrs/C-ave-0-8 hrs at steady state is 1.2 to 1.6.

In one embodiment of any of the above aspects, administration of asingle dose of the composition to a human subject provides a plasmaconcentration profile characterized by: a fractional AUC from 0 to 4hours that is less than 5%, and preferably less than 3% of AUC_(0-inf);a fractional AUC from 0 to 8 hours that is about 5 to 15%, andpreferably about 8 to 12% of AUC_(0-inf); a fractional AUC from 0 to 12hours that is about 10 to 40%, and preferably about 15 to 30% ofAUC_(0-inf); a fractional AUC from 0 to 18 hours that is about 25 to60%, and preferably about 30 to 50% of AUC_(0-inf); and a fractional AUCfrom 0 to 24 hours that is about 40 to 75%, and preferably about 50 to70% of AUC_(0-inf).

In one embodiment of any of the above aspects, a once daily oraladministration of the composition to a human subject provides a steadystate plasma concentration profile characterized by: a fractional AUCfrom 0 to 4 hours that is about 2 to 25%, and preferably about 5 to 20%of AUC₂₄; a fractional AUC from 0 to 8 hours that is about 15 to 50%,and preferably about 20 to 40% of AUC₂₄; a fractional AUC from 0 to 12hours that is about 30 to 70%, and preferably about 40 to 60% of AUC₂₄:and a fractional AUC from 0 to 18 hours that is about 60 to 95%, andpreferably about 75 to 90% of AUC₂₄.

In one embodiment of any of the above aspects, a once daily oraladministration of the composition to a human subject provides a steadystate plasma concentration profile characterized by: a fractional AUCfrom 0 to 8 hours that is about 15 to 40%, and preferably about 20 to32% of AUC₂₄; a fractional AUC from 8 to 16 hours that is about 30 to50%, and preferably about 35 to 45% of AUC₂₄; and a fractional AUC from16 to 24 hours that is about 20 to 35%, and preferably about 25 to 33%of AUC₂₄.

In one embodiment of any of the above aspects the amantadine isadministered as a pharmaceutically acceptable salt. In a more specificembodiment, the amantadine is administered as hydrochloride oramantadine sulfate.

In one embodiment of any of the above aspects, a total daily dose of 50mg to 600 mg of amantadine, or a pharmaceutically acceptable saltthereof is administered to a patient. More specifically the daily doseof amantadine or pharmaceutically acceptable salt thereof administeredmay be in the range of 100 to 440 mg. In another specific embodiment,the daily dose of amantadine or pharmaceutically acceptable salt thereofmaybe in the range of 260 to 420 mg. In another embodiment, the dailydose of amantadine or pharmaceutically acceptable salt thereofadministered exceeds 300 mg per day. In various specific embodiments,the daily dose of amantadine or pharmaceutically acceptable salt thereofmay be 50 to 75 mg, 70 to 95 mg, 90 to 115 mg, 110 to 135 mg, 130 to 155mg, 150 to 175 mg, 170 to 195 mg, 190 to 215 mg, 210 to 235 mg, 230 to255 mg, 250 to 275 mg, 270 to 295 mg, 290 to 305 mg, 300 to 315 mg, 310to 325 mg, 320 to 335 mg, 330 to 345 mg, 340 to 355 mg, 350 to 365 mg,360 to 375 mg, 370 to 385 mg, 380 to 395 mg, 390 to 405 mg, 400 to 415mg, 410 to 425 mg, 420 to 435 mg, 430 to 445 mg or 440 to 455 mg.

In one embodiment of any of the above aspects, the composition comprises50 mg to 600 mg of amantadine, or a pharmaceutically acceptable saltthereof. More specifically, the composition may comprise 100 mg to 450mg of amantadine, or a pharmaceutically acceptable salt thereof. Stillmore specifically, the composition may comprise 130-210 mg ofamantadine, or a pharmaceutically acceptable salt thereof. In variousspecific embodiments, a dosage form containing the composition comprises50 to 75 mg, 70 to 95 mg, 90 to 115 mg, 110 to 135 mg, 130 to 155 mg,150 to 175 mg, 170 to 195 mg, 190 to 215 mg, 210 to 235 mg, 230 to 255mg, 250 to 275 mg, 270 to 295 mg, 290 to 305 mg, 300 to 315 mg, 310 to325 mg, 320 to 335 mg, 330 to 345 mg, 340 to 355 mg, 350 to 365 mg, 360to 375 mg, 370 to 385 mg, 380 to 395 mg, 390 to 405 mg, 400 to 415 mg,410 to 425 mg, 420 to 435 mg, 430 to 445 mg or 440 to 455 mg ofamantadine, or a pharmaceutically acceptable salt thereof. In a morespecific embodiment, the composition comprises about 110, 120, 130, 140,150, 160 170, 180, 190, 210, or 220 mg amantadine, or a pharmaceuticallyacceptable salt thereof. In another more specific embodiment, thecomposition comprises 110 mg amantadine hydrochloride. In another morespecific embodiment, the composition comprises 130 mg amantadinehydrochloride. In another more specific embodiment, the compositioncomprises 170 mg amantadine hydrochloride. In another more specificembodiment, the composition comprises 210 mg amantadine hydrochloride.

In one embodiment of any of the above aspects, the composition isadministered as one, two, three or four unit dosage forms eachcomprising 100 to 175 mg amantadine, or a pharmaceutically acceptablesalt thereof. In a more specific embodiment, the composition isadministered as two unit dosage forms each comprising 100 to 175 mgamantadine, or a pharmaceutically acceptable salt thereof.

In one embodiment of any of the above aspects, the composition isadministered as one, two, or three unit dosage forms each comprising 50to 250 mg amantadine, or a pharmaceutically acceptable salt thereof. Ina more specific embodiment, the composition is administered as one ortwo unit dosage forms each comprising 65 to 220 mg amantadine, or apharmaceutically acceptable salt thereof.

In one embodiment of any of the above aspects, oral administration of asingle dose of the composition to a human subject in a fasted stateprovides a maximum plasma concentration (Cmax) of 1.0 to 2.8 ng/ml permg of amantadine. In a more specific embodiment, oral administration ofa single dose of the composition to a human subject in a fasted stateprovides a maximum plasma concentration (Cmax) of 1.6 to 2.4 ng/ml permg of amantadine and an AUC_(0-inf). (Area under the concentration-curvecurve from t=0 to t=infinity) of 40 to 75 ng*h/mL per mg of amantadine.

In one embodiment of any of the above aspects, the daily oraladministration of a dose of the composition to a human subject providesa steady state plasma concentration profile characterized by at leastone of: (i) a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine, (ii) a Cminof 1.1 to 2.6 ng/ml per mg of amantadine, and (iii) an AUC₀₋₂₄ of 44 to83 ng*h/mL per mg of amantadine. In a more specific example, all threecriteria of (i), (ii) and (iii) are met.

In a more specific embodiment, the steady state plasma concentrationprofile is further characterized by: (iv) no increase in concentrationof amantadine for at least one hour after the administration; and (v)Cmax/Cmin ratio of 1.5 to 2.0. In a more specific embodiment, bothcriteria of (iv) and (v) are met.

In another more specific embodiment, the steady state plasmaconcentration profile is further characterized by at least one of: (iv)no increase in plasma concentration of amantadine for at least two hoursafter the administration; and (v) a Cmax/Cmin ratio of 1.7 to 1.9. In amore specific embodiment, both criteria of (iv) and (v) are met.

In one embodiment of any of the above aspects the composition has an invitro dissolution profile of amantadine which shows at least one of (i)not more than 25% dissolution at 2 hours, (ii) not more 55-85%dissolution at 6 hours, and (iii) at least 80% dissolution at 12 hours,using a USP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37° C.as the dissolution medium. In a more specific embodiment two of criteria(i), (ii) and (iii) are met. In a more specific embodiment, all three ofcriteria (i), (ii) and (iii) are met.

In one embodiment of any of the above aspects the composition has an invitro dissolution profile of amantadine which shows at least one of (i)not more than 25% dissolution at 2 hours, (ii) not more than 25-55%dissolution at 6 hours, and (iii) at least 80% dissolution at 12 hours,using a USP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37° C.as the dissolution medium. In a more specific embodiment two of criteria(i), (ii) and (iii) are met. In a more specific embodiment, all three ofcriteria (i), (ii) and (iii) are met.

In one embodiment of any of the above aspects the composition has an invitro dissolution profile of amantadine which shows at least one of (i)not more than 20% dissolution at 1 hour, (ii) about 25-45% dissolutionat 2 hours, (iii) not more than 50-80% dissolution at 4 hours, and (iv)at least 80% dissolution at 8 hours, using a USP Apparatus II (Paddles)at 50 rpm with 500 ml water at 37° C. as the dissolution medium. In amore specific embodiment two of criteria (i), (ii), (iii) and (iv) aremet. In a more specific embodiment, all four of criteria (i), (ii),(iii) and (iv) are met.

In one embodiment of any of the above aspects the in vitro dissolutionprofile of amantadine is further characterized by release of amantadineof: (i) not more than 10% at 1 hour, or (ii) 30-50% at 4 hours, or (iii)at least 90% at 12 hours using a USP Apparatus II (Paddles) at 50 rpmwith 500 ml water at 37° C. as the dissolution medium. In a morespecific embodiment two of criteria (i), (ii) and (iii) are met. In amore specific embodiment, all three criteria of (i), (ii) and (iii) aremet.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising or consisting of a pellet-in-capsule, wherein apellet comprises a core that comprises a core seed with a mixture ofamantadine and a binder coated onto the core seed, and an extendedrelease coating surrounding the core comprising ethyl cellulose, a poreforming agent such as hydroxypropyl methyl cellulose or povidone, and aplasticizer.

In another aspect, the present invention provides a pharmaceuticalcomposition for use in the methods of the aspects described above,wherein said composition is for oral administration and comprises acapsule for oral administration, said capsule comprising a plurality ofpellets, each pellet comprising: (a) a pellet core comprisingamantadine, or a pharmaceutically acceptable salt thereof, and (b) anextended release coating surrounding the pellet core.

In one embodiment, the extended release coating comprises ethylcellulose and at least one of povidone and hydroxypropyl methylcellulose, and a plasticizer. In a more specific embodiment, theextended release coating comprises ethyl cellulose, povidone, and aplasticizer.

In one embodiment, the pellet core comprises amantadine and a bindercoated onto a core seed. In one embodiment, the core seed is a sugarsphere (nonpareil) or microcrystalline cellulose seed (e.g. Celphere®).In a more specific embodiment, the core seed is a microcrystallinecellulose core. In another specific embodiment, the core seed has adiameter in the range of 100 microns to 1,000 microns. In additionalspecific embodiments, the core seed has a diameter of 100, 200, 300,400, 500, 600 or 700 microns. In preferred specific embodiments, thecore seed has a diameter of less than 500 microns.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the amantadine, or a pharmaceuticallyacceptable salt thereof, is present in amounts from 20 to 80 wt %, witha bulk density of 0.3 to 1.2 g/cm³.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the amantadine, or a pharmaceuticallyacceptable salt thereof, is present in amounts from 40 to 60 wt %, witha bulk density of 0.5 to 1.2 g/cm³.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the amantadine, or a pharmaceuticallyacceptable salt thereof, is present in amounts from 60 to 80 wt %, witha bulk density of 0.5 to 1.2 g/cm³.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the binder is present in amounts from 8 to 25wt %.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the core seed is present in amounts from 8 to25 wt %.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the ethyl cellulose is present in amounts from10 to 20 wt %.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the povidone is present in amounts from 1 to 4wt %.

In one embodiment, based on the combined weight of the pellet core andextended release coating, and the plasticizer is present in amounts from1 to 4 wt %.

In one embodiment, the coated pellet has a diameter in the range of 200microns to 1700 micros. In additional specific embodiments, the coatedpellet has a diameter of 200, 300, 400, 500, 600, 700, 800, 900, 1000,1100, 1200, 1300 or 1500 microns. In certain specific embodiments, thecoated pellet has a diameter of less than 1000 microns, e.g., from 500to 1000 microns.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the binder is present in amounts from 5 to 25wt %.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the core seed is present in amounts from 1 to15 wt %.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the ethyl cellulose is present in amounts from5 to 20 wt %.

In one embodiment, based on the combined weight of the pellet core andextended release coating, the povidone is present in amounts from 0.25to 4 wt %.

In one embodiment, based on the combined weight of the pellet core andextended release coating, and the plasticizer is present in amounts from0.25 to 4 wt %.

In one embodiment, the pellet further comprises a seal coating betweenthe pellet core and the extended release coating. In some embodiments,an inert coating can be applied to the inert core prior to drug coatingor on drug-coated pellets or on controlled release coated pellets. Inanother embodiment, an enteric coating can be applied to the drug coatedpellets or controlled release pellets.

In one embodiment, the pellet core comprises a binder, selected from thegroup consisting of hydroxypropyl methyl cellulose, copovidone, andmixtures thereof.

In one embodiment, the above composition is provided in a size 3, size2, size 1, size 0 or size 00 capsule.

In one embodiment, the therapeutically effective daily dose of the abovecomposition is administered in no more than two capsules. In anotherembodiment, the therapeutically effective daily dose of the compositionis administered in no more than three size 1 capsules. In anotherembodiment, the therapeutically effective daily dose of the compositionis administered in no more than two size 0 capsules. In a still morepreferred embodiment, the therapeutically effective daily dose of thecomposition is administered in no more than two size 1 capsules. Inanother embodiment, the therapeutically effective daily dose of thecomposition is administered in no more than three size 2 capsules.

In a preferred embodiment, the above composition is provided in anamount of 50 to 110 mg of amantadine or a pharmaceutically acceptablesalt thereof in a size 2 capsule, and in the amount of 110 mg to 210 mgof amantadine or a pharmaceutically acceptable salt thereof in a size 1capsule. In additional embodiments, the above composition comprisescoated pellets of diameter 300 to 1000 microns, with amantadine orpharmaceutically acceptable salt thereof content of 40-80% wt % and at abulk density of 0.5-1.2 g/cm³. In a further preferred embodiment, theabove composition has an in vitro dissolution profile of amantadinewhich shows at least one of (i) not more than 25% dissolution at 2hours, (ii) not more than 55-85% dissolution at 6 hours, and (iii) atleast 80% dissolution at 12 hours, using a USP Apparatus II (Paddles) at50 rpm with 500 ml water at 37° C. as the dissolution medium. In a morespecific embodiment two of criteria (i), (ii) and (iii) are met. In amore specific embodiment, all three of criteria (i), (ii) and (iii) aremet.

In one embodiment, the plasticizer is selected from the group consistingof medium chain triglycerides, diethyl phthalate, citrate esters,polyethylene glycol, glycerol, acetylated glycerides, and castor oil. Ina more specific embodiment, the plasticizer is medium chaintriglycerides, e.g. Miglyol 812 N.

In another aspect, the present invention provides method ofadministering amantadine, or a pharmaceutically acceptable salt thereof,to a human subject in need thereof, said method comprising orallyadministering a composition of any of the above aspects.

In another aspect, the present invention provides a method of treatingParkinson's disease in a human subject in need thereof, said methodcomprising orally administering a composition of any of the aboveaspects. In a preferred aspect, the present invention provides a methodof treating disease in a human subject in need thereof, said methodcomprising orally administering a composition of any of the aboveaspects once daily at nighttime, administering 1, 2 or 3 capsules.

References to administering amantadine to a subject in need thereofinclude treating a patient with a disease or condition which may betreated, prevented or cured by a NMDA antagonist. More specifically,administering amantadine to a subject in need thereof includes treatinga patient with Parkinson's Disease, brain injury, brain trauma,dementia, Alzheimer's disease, stroke, Huntington's disease, ALS,Multiple Sclerosis, neurodegenerative diseases, dementias,cerebrovascular conditions, movement disorders, cranial nerve disorders,neuropsychiatric disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution profiles for three amantadine ERformulations, A, B, C referred to in Example 3.

FIGS. 2A and 2B show the mean plasma concentration-time curves afteradministration of amantadine IR twice daily (A) and amantadine ER oncedaily (B) to healthy, adult, male and female subjects under fastingconditions on days 1 and 9.

FIG. 3 shows a plot of mean plasma concentration of amantadine versustime curves after administration of amantadine IR twice daily andamantadine ER once daily to healthy, adult, male and female subjectsunder fasting conditions on day 9.

FIG. 4 shows the simulated mean plasma concentration of amantadineversus time curves following multiple dose administration of variousstrengths of immediate release amantadine dosed twice or thrice dailyand various strengths of amantadine ER administered once daily.

FIG. 5 shows a plot of mean (SD) plasma amantadine concentrations versusscheduled time for four (4) amantadine treatments.

FIG. 6 shows a semi-logarithmic mean (SD) plasma amantadineconcentrations versus scheduled time for four (4) amantadine treatments.

FIG. 7 shows simulated steady state plasma concentration time profilesfor the ER amantadine formulations as described in Example 12. The ERamantadine formulation 2, administered once daily at night, results atsteady state in about 4 hour delay in achieving peak plasmaconcentration relative to formulation 1.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a method of reducing sleep disturbances in apatient undergoing treatment with amantadine. The method comprisesadministering amantadine to a patient in need thereof, such that theamantadine does not interfere with sleep, yet provides maximum benefitin morning hours when often needed most by many patients who takeamantadine and further, provides nighttime coverage of symptoms ofParkinson's disease if needed. Nighttime coverage includes providingbenefit if the patient wakes up and wishes to return to sleep.

The method of the invention comprises orally administering to thepatient an extended release (ER) amantadine composition designed fornighttime administration. The composition is taken less than three hoursbefore bedtime, and preferably less than two and a half, less than two,less than one and a half, or less than one hour before bedtime. Mostpreferably the ER amantadine composition is taken less than half hourbefore bedtime (i.e. the time at which the subject wishes to go to sleepfor the night). As used herein, a reference to amantadine is intended toencompass pharmaceutically acceptable salts thereof (e.g. amantadinehydrochloride, amantadine sulfate, etc.). Alternatively, the compositionis administered less than about 4 hours before bedtime.

As used herein, “extended release” includes “controlled release”,“modified release”, “sustained release”, “timed release”, “delayedrelease”, and also mixtures of delayed release, immediate release,enteric coated, etc. with each of the above.

The patient may be diagnosed with any disease or disorder for whichamantadine is prescribed, such as Parkinson's disease, multiplesclerosis, drug-induced extrapyramidal reactions, levodopa-induceddyskinesia, and viral diseases (e.g. influenza, HBV, and HCV). In aspecific embodiment, the patient has Parkinson's disease, which, as usedherein, also encompasses a diagnosis of parkinsonism. In one embodiment,the patient has early stage Parkinson's disease, and the amantadine isused as a monotherapy or in combination with a monoamine oxidase type B(MAO-B) inhibitor without concomitant use of levodopa. In anotherembodiment, the patient has late stage Parkinson's disease and thepatient takes levodopa in addition to the amantadine. In anotherembodiment, the patient has multiple sclerosis and the amantadine isused for the treatment of fatigue. In other embodiments, the patient hasa brain injury, brain injury, brain trauma, dementia, Alzheimer'sdisease, stroke, Huntington's disease, ALS, Multiple Sclerosis,neurodegenerative diseases, dementias, cerebrovascular conditions,movement disorders, cranial nerve disorders, neuropsychiatric disorders.

An ER amantadine composition for use in the invention is adapted fornighttime administration by providing a plasma concentration profilethat does not interfere with the subject's sleep. The composition of theinvention will, upon administration to a human subject, result in agradual initial increase in plasma concentration of amantadine suchthat, at steady state conditions, administration of a dose of thecomposition results in an increase in plasma concentration of amantadineof less than 25% at three hours after the dose is administered. Forexample, if a subject's steady state plasma concentration of amantadineis 500 ng/ml at the time a dose of the composition is administered,three hours later the subject's plasma concentration of amantadine willbe less than 625 ng/ml. Preferably, the increase in plasma concentrationof amantadine is less than 15%, and most preferably, less than 10%.Particularly preferred compositions have a plasma concentration profilefurther characterized by no increase in amantadine plasma concentration,or even a decrease (at steady state conditions), for at least one or, ina preferred embodiment, two hours after the administration. Thecomposition for use in the invention is further adapted for bedtime(i.e. the time at which the subject wishes to go to sleep for the night)administration by providing a maximum concentration of amantadine (Cmax)in the morning hours. The time to reach Cmax (Tmax), as measured aftersingle dose administration in the fasted state, is at least, 8 hours andup to 13, 14, 15, or 16 hours, or at least 9 hours and up to 13, 14, 15,or 16 hours, or at least 10 hours, and up to 13, 14, 15, or 16 hours. Inspecific embodiments, the Tmax is 9 to 15 hours, preferably 10 to 14hours, and most preferably 11 to 13 hours. At steady state, with oncedaily administration of the composition, the Tmax is 7 to 13 hours,preferably 8 to 12 hours, and most preferably 9 to 11 hours. A suitableER amantadine composition may be further characterized by having asteady-state Cmax/Cmin ratio of 1.5 to 2.0, and preferably 1.7 to 1.9,resulting in a composition with optimal fluctuation.

In more specific, preferred embodiments, the plasma concentrationprofile is further characterized by having an AUC profile afteradministration of a single dose of the composition characterized by: afractional AUC from 0 to 4 hours that is less than 5%, and preferablyless than 3% of AUC_(0-inf); a fractional AUC from 0 to 8 hours that isabout 5 to 15%, and preferably about 8 to 12% of AUC_(0-inf); afractional AUC from 0 to 12 hours that is about 10 to 40%, andpreferably about 15 to 30% of AUC_(0-inf); a fractional AUC from 0 to 18hours that is about 25 to 60%, and preferably about 30 to 50% ofAUC_(0-inf); and a fractional AUC from 0 to 24 hours that is about 40 to75%, and preferably about 50 to 70% of AUC_(0-inf).

In a further preferred embodiment, the plasma concentration profile isfurther characterized by having an AUC profile after once daily dosingof the composition at steady state conditions characterized by: afractional AUC from 0 to 4 hours that is about 2 to 25%, and preferablyabout 5 to 20% of AUC₂₄; a fractional AUC from 0 to 8 hours that isabout 15 to 50%, and preferably about 20 to 40% of AUC₂₄; a fractionalAUC from 0 to 12 hours that is about 30 to 70%, and preferably about 40to 60% of AUC₂₄: and a fractional AUC from 0 to 18 hours that is about60 to 95%, and preferably about 75 to 90% of AUC₂₄.

In some embodiments of any of the above aspects, the steady state plasmaconcentration profile following multiple administrations to a humansubject of the composition at bedtime is characterized by an averageplasma concentration during the day (“C-ave-day”, defined as the averageday time amantadine plasma concentration as measured in a human PKstudy) that is 1.1 to 2.0 times the average plasma concentration duringthe night (“C-ave-night”, defined as the average night time amantadineplasma concentration as measured in a human PK study). In someembodiments, the ratio of C-ave-day/C-ave-night at steady state iswithin one of the ranges 1.1 to 1.9, 1.1 to 1.8, 1.1 to 1.7, 1.1 to 1.6,1.1 to 1.5, 1.1 to 1.4, 1.2 to 1.9, 1.2 to 1.7, 1.2 to 1.6, 1.2 to 1.5,1.3 to 1.9, 1.3 to 1.8, 1.3 to 1.7, 1.3 to 1.6, 1.4 to 1.9, 1.4 to 1.8,1.4 to 1.7, 1.5 to 1.9, 1.5 to 1.8, 1.5 to 1.7, 1.6 to 1.9, 1.6 to 1.8or 1.7 to 1.9. In some embodiments, the ratio of C-ave-day/C-ave-nightat steady state is 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5,1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95, or 2.0. In someembodiments, the C-ave-day is the average amantadine plasmaconcentration as measured between the hours of 5 am, 6 am, 7 am, 8 am or9 am to the hours of 4 pm, 5 pm, 6 pm, 7 pm or 8 pm and the C-ave-nightis the average amantadine plasma concentration as measured between thehours of 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, 9 pm, 10 pm or 11 pm to the hoursof 5 am, 6 am, 7 am, 8 am or 9 am. In some embodiments, the C-ave-day isthe average amantadine plasma concentration as measured within any fourto twelve hour period between the hours of 5 am and 8 pm; and theC-ave-night is the average amantadine plasma concentration as measuredwithin any four to twelve hour period between the hours of 8 pm and 5am. In some embodiments, the C-ave-day is the average amantadine plasmaconcentration as measured within any four, five, six, seven, eight,nine, ten, eleven or twelve hour period between the hours of 5 am and 8pm; and the C-ave-night is the average amantadine plasma concentrationas measured within any four, five, six, seven, eight, nine, ten, elevenor twelve hour period between the hours of 8 pm and 5 am.

In some embodiments described herein an amantadine composition isadministered to a patient from 0 to 4 hours prior to bedtime. In someembodiments, the amantadine composition is administered to a patientfrom 0 to 3, 0 to 2 or 0 to 1 hours prior to bedtime. In someembodiments, the amantadine composition is administered to a patientfrom 0 to 240 minutes, from 0 to 180 minutes, e.g. from 0 to 120minutes, from 0 to 60 minutes, from 0 to 45 minutes, from 0 to 30minutes, from 0 to 15 minutes or from 0 to 10 minutes prior to bedtime.In some embodiments, the amantadine composition is administered to apatient from 60 to 240 minutes, from 60 to 180 minutes, from 60 to 120minutes or from 60 to 90 minutes prior to bedtime.

It is to be understood that administration to a patient includesadministration by a healthcare professional and self administration bythe patient.

Unless otherwise specified herein, the term “bedtime” has the normalmeaning of a time when a person retires for the primary sleep periodduring a twenty-four hour period of time. While for the generalpopulace, bedtime occurs at night, there are patients, such as those whowork nights, for whom bedtime occurs during the day. Thus, in someembodiments, bedtime may be anytime during the day or night.

As used herein, unless otherwise indicated, reference to a plasmaconcentration profile or a specific pharmacokinetic property (e.g. Cmax,Cmin, AUC, Tmax, etc.) in a human subject refers to a mean valueobtained from healthy adults s determined in a typical phase I clinicaltrial designed to measure pharmacokinetic properties of a drug (see e.g.Examples 5, 6 and 7, below). References herein to Tmax refer to valuesobtained after administration of a single dose at fasted states, unlessotherwise indicated.

In some embodiments of the invention, the dose of the amantadineadministered in accordance with the present invention is within or abovethe ranges normally prescribed for immediate release compositions ofamantadine. In other embodiments, the doses of the amantadineadministered with the present invention are higher than the rangesnormally prescribed for immediate release compositions of amantadine.For example, the recommended dose of amantadine for the treatment ofParkinson's disease is 100 mg administered twice daily. In limited casesof the patient not deriving sufficient benefit at that dose and subjectto the patient being able to tolerate such higher dose, the dose may beincreased to 300 mg or 400 mg in divided doses. The most commonlyprescribed doses of amantadine are 100 mg to 200 mg per day, with thelatter administered in divided doses. More than 200 mg (for example 300mg) is always given in divided doses. For the present invention, dosesof 50 to 600 mg, or more preferably, 200 to 450 mg are administered fortreatment of Parkinson's disease, and the methods and compositions ofthe invention may comprise administration of a dose as defined by any ofthese ranges. In specific embodiments the administration of such higherdoses may be once daily. In additional embodiments the administration ofsuch higher doses may be at night. In additional embodiments theadministration of such higher doses may be in the form of 1, 2 or 3capsules of size 0, 1 or 2 administered once daily.

In one embodiment of any of the above aspects the amantadine isadministered as a pharmaceutically acceptable salt. In a more specificembodiment, the amantadine is administered as hydrochloride oramantadine sulfate.

In one embodiment of any of the above aspects, a total daily dose of 50mg to 600 mg of amantadine, or a pharmaceutically acceptable saltthereof is administered to a patient. More specifically the daily doseof amantadine or pharmaceutically acceptable salt thereof administeredmay be in the range of 100 mg to 440 mg. In another specific embodiment,the daily dose of amantadine or pharmaceutically acceptable salt thereofmaybe in the range of 260 mg to 420 mg. In another embodiment, the dailydose of amantadine or pharmaceutically acceptable salt thereofadministered exceeds 300 mg per day. In various specific embodiments,the daily dose of amantadine or pharmaceutically acceptable salt thereofmay be 50 to 75 mg, 70 to 95 mg, 90 to 115 mg, 110 to 135 mg, 130 to 155mg, 150 to 175 mg, 170 to 195 mg, 190 to 215 mg, 210 to 235 mg, 230 to255 mg, 250 to 275 mg, 270 to 295 mg, 290 to 305 mg, 300 to 315 mg, 310to 325 mg, 320 to 335 mg, 330 to 345 mg, 340 to 355 mg, 350 to 365 mg,360 to 375 mg, 370 to 385 mg, 380 to 395 mg, 390 to 405 mg, 400 to 415mg, 410 to 425 mg, 420 to 435 mg, 430 to 445 mg or 440 to 455 mg.

In one embodiment of any of the above aspects, the composition comprises50 to 600 mg of amantadine, or a pharmaceutically acceptable saltthereof. More specifically, the composition may comprise 100 to 450 mgof amantadine, or a pharmaceutically acceptable salt thereof. Still morespecifically, the composition may comprise 130-210 mg of amantadine, ora pharmaceutically acceptable salt thereof. In various specificembodiments, the dosage form comprises 50 to 75 mg, 70 to 95 mg, 90 to115 mg, 110 to 135 mg, 130 to 155 mg, 150 to 175 mg, 170 to 195 mg, 190to 215 mg, 210 to 235 mg, 230 to 255 mg, 250 to 275 mg, 270 to 295 mg,290 to 305 mg, 300 to 315 mg, 310 to 325 mg, 320 to 335 mg, 330 to 345mg, 340 to 355 mg, 350 to 365 mg, 360 to 375 mg, 370 to 385 mg, 380 to395 mg, 390 to 405 mg, 400 to 415 mg, 410 to 425 mg, 420 to 435 mg, 430to 445 mg or 440 to 455 mg of amantadine, or a pharmaceuticallyacceptable salt thereof. In a more specific embodiment, the compositioncomprises about 110, 120, 130, 140, 150, 160 170, 180, 190, 210, or 220mg amantadine, or a pharmaceutically acceptable salt thereof. In anothermore specific embodiment, the composition comprises 110 mg amantadinehydrochloride. In another more specific embodiment, the compositioncomprises 130 mg amantadine hydrochloride. In another more specificembodiment, the composition comprises 170 mg amantadine hydrochloride.In another more specific embodiment, the composition comprises 210 mgamantadine hydrochloride.

In one embodiment of any of the above aspects, the composition comprisesfrom about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,220 mg, 230 mg, 240 mg, 250 mg, 260 mg of amantadine, or apharmaceutically acceptable salt thereof to about 75 mg, 85 mg, 95 mg,105 mg, 115 mg, 125 mg, 135 mg, 145 mg, 155 mg, 165 mg, 175 mg, 185 mg,195 mg, 205 mg, 215 mg, 225 mg, 235 mg, 245 mg, 255 mg, 265 mg, 275 mg,285 mg, 295 mg, 305 mg, 315 mg, 325 mg, 335 mg, 345 mg, 355 mg, 365 mg,375 mg, 385 mg, 395 mg, 405 mg, 415 mg, 425 mg, 435 mg, 445 mg ofamantadine, or a pharmaceutically acceptable salt thereof.

In a specific embodiment of the invention, a subject's entire daily doseof amantadine is administered once, during a period of less than aboutthree, two or one hours before bedtime (i.e. the time at which thesubject wishes to go to sleep for the night). In other embodiments, atleast one half of the daily dose of amantadine is taken during saidperiod before bedtime. Preferably at least ⅔ of the dose of amantadineis taken in said period before bedtime, with the remainder taken inmorning or afternoon. The morning or afternoon dose of the amantadinemay be provided in a conventional, immediate release dosage form, or inan extended release form.

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in levodopa induced dyskinesia. In a specific embodiment,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% reductionin levodopa induced dyskinesia. In further embodiments, the reduction inlevodopa induced dyskinesia is measured on a numeric scale that is usedby or accepted by the FDA or other regulatory agencies to evaluate theeffectiveness of and to approve for licensure drugs for the treatment ofLID. In further specific embodiments, the scale used in measuring thereduction in LID could be UDysRS, UPDRS Part IV (subscores 32, 33),Dyskinesia Rating Scale (DRS), Abnormal Involuntary Movement Scale(AIMS), Rush Dyskinesia Rating Scale, Parkinson Disease Dyskinesia Scale(PDYS-26), Obeso Dyskinesia Rating Scale (CAPIT), Clinical DyskinesiaRating Scale (CDRS), Lang-Fahn Activities of Daily Living Dyskinesia orother scales developed for this purpose.

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in Parkinson's disease fatigue. In a specific embodiment,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% reduction in Parkinson'sdisease fatigue. In further specific embodiments, the reduction infatigue is measured on a numerical scale used by or accepted by the FDAor other regulatory agencies to evaluate the effectiveness of and toapprove for licensure drugs for the treatment of fatigue. In furtherspecific embodiments, the scale used in measuring the reduction infatigue could be the Fatigue Severity Scale (FSS), Fatigue AssessmentInventory, Functional Assessment of Chronic Illness Therapy-Fatigue(FACIT Fatigue), Multidimensional Fatigue Inventory (MFI-20), ParkinsonFatigue Scale (PFS-16) and the Fatigue Severity Inventory. In otherspecific embodiments, the reduction in fatigue is measured relative toplacebo in a controlled clinical trial. In other embodiments, thereduction in fatigue is measured relative to baseline in a controlledclinical trial.

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in Parkinson's disease symptoms. In a specific embodiment,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, or 40% reduction in Parkinson's symptoms. In furtherspecific embodiments, the reduction in Parkinson's symptoms is measuredon a numerical scale used by or accepted by the FDA or other regulatoryagencies to evaluate the effectiveness of and to approve for licensuredrugs for the treatment of Parkinson's symptoms. In further specificembodiments, the scale used in measuring the reduction in Parkinson'ssymptoms could be the Unified Parkinson's Disease Rating Scale (UPDRS).Unified Parkinson's Disease Rating Scale (UPDRS, MDS revision)—Part I:non-motor aspects of experiences of daily living (13 items), Part II:motor aspects of experiences of daily living (13 items)—Part III: motorexamination (33 scored items)—Part I: mental status, behavior andmood—Part II: activities of daily living—Part III: motor examination (27scored items) Hoehn and Yahr Staging Scale (Original or Modified).

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in levodopa induced dyskinesia. In a specific embodiment,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% reductionin levodopa induced dyskinesia. In further embodiments, the reduction inlevodopa induced dyskinesia is measured on a numeric scale that is usedby the FDA to evaluate effectiveness of drugs indicated to reduce LID.In further specific embodiments, the scale used in measuring thereduction in LID could be UDysRS, UPDRS Part IV (subscores 32, 33),Dyskinesia Rating Scale (DRS), Abnormal Involuntary Movement Scale(AIMS), or other scales developed for this purpose. In other specificembodiments, the reduction in LID is measured relative to placebo in acontrolled clinical trial. In other embodiments, the reduction in LID ismeasured relative to baseline in a controlled clinical trial.

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in Parkinson's disease fatigue. In a specific embodiment,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, or 40% reduction in Parkinson's disease fatigue. Infurther specific embodiments, the reduction fatigue is measured on anumeric scale that is used by the FDA to evaluate effectiveness of drugsindicated to reduce fatigue. In further specific embodiments, the scaleused in measuring the reduction in fatigue could be the Fatigue SeverityScale (FSS). In other specific embodiments, the reduction in fatigue ismeasured relative to placebo in a controlled clinical trial. In otherembodiments, the reduction in fatigue is measured relative to baselinein a controlled clinical trial.

In one embodiment of any of the above aspects, administration of thecomposition to a Parkinson's disease patients results in a significantreduction in Parkinson's disease symptoms. In a specific embodiment,administration of the composition results in about 5%, 10%, 15%, 20%,25%, 30%, 35%, or 40% reduction in Parkinson's symptoms. In furtherspecific embodiments, the reduction in Parkinson's symptoms is measuredon a numeric scale that is used by the FDA to evaluate effectiveness ofdrugs indicated to reduce Parkinson's symptoms. In further specificembodiments, the scale used in measuring the reduction in Parkinson'ssymptoms could be the Unified Parkinson's Disease Rating Scale (UPDRS).In other specific embodiments, the reduction in Parkinson's diseasesymptoms is measured relative to placebo in a controlled clinical trial.In other embodiments, the reduction in Parkinson's disease symptoms ismeasured relative to baseline in a controlled clinical trial.

Extended Release Formulations

Extended release amantadine compositions suitable for use in the methodof the invention can be made using a variety of extended releasetechnologies, such as those described in the patent publicationsreferenced in the above background section, which publications areincorporated herein by reference in their entireties. In someembodiments, the invention is a pellet in capsule dosage form. In someembodiments, the pellets comprise a pellet core, which is coated with atleast one drug layer and at least one extended release coating layer. Insome embodiments, the pellets are coated with at least one drug layer,an intermediate layer such as a seal coat and an extended releasecoating layer. In some embodiments, the pellet, the drug layer or bothcomprise one or more binders.

In some embodiments, the dosage unit comprises a plurality of coatedpellets. In some embodiments, the pellets have a diameter of for example300 to 1700 microns, in some cases 500 to 1200 microns. The pellets willcomprise, for example, inert substrates, such as sugar spheres,microcrystalline cellulose (MCC) spheres, starch pellets. In someembodiments, pellets can be prepared by other processes such aspelletization, extrusion, spheronization, etc. or combinations thereof.The core pellets will comprise of amantadine hydrochloride andpharmaceutically acceptable excipients.

Coated Pellets

The pellet cores are coated with the active ingredient, e.g., amantadineor a pharmaceutically acceptable salt and/or polymorph thereof. In someembodiments, in addition to the active ingredient, the pellets alsocomprise one or more binders, such as for example hydroxypropyl methylcellulose, copovidone, povidone, hydroxypropyl cellulose, hydroxyethylcellulose, methyl cellulose, carboxymethyl cellulose etc. In someembodiments, the pellets also contain one or more additional excipients,such as anti-tack agents (e.g. talc, magnesium stearate etc.)

In some embodiments, the pellets cores are coated with a drug layercomprising active ingredient, and optionally one or more binders,anti-tack agents and/or solvents by conventional coating techniques suchas fluidized bed coating, pan coating.

Intermediate Layer Coating

In some embodiments, the pellets are coated with an intermediate layer,such as a seal coat. In some embodiments, the seal coat is adapted toprevent ingredients in the extended release coating from interactingwith ingredients in the pellet core, to prevent migration of theingredients in the pellet core from diffusing out of the pellet coreinto the extended release layer, etc. As described herein, the seal coatof the present invention can comprise one or more film forming polymersincluding but not limited to hydroxypropylmethyl cellulose (HPMC),copovidone, povidone, polyvinyl pyrrolidone, hydroxypropyl cellulose,hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose or anycombination thereof and the like.

The seal coat can further comprise other additives like plasticizers,such as, propylene glycol, triacetin, polyethylene glycol, tributylcitrate and optionally anti-tacking agents, such as, magnesium stearate,calcium silicate, magnesium silicate, and colloidal silicon dioxide ortalc.

Apart from plasticizers and anti-tacking agents as mentioned above, theseal coat can optionally contain buffers, colorants, opacifiers,surfactants or bases, which are known to those skilled in the art.

Seal coating can be applied to the core using conventional coatingtechniques such as fluidized bed coating, pan coating etc. In someembodiments, the drug coated pellets cores are coated with a seal coatlayer that optionally comprises one or more binders, anti-tack agentsand/or solvents by fluidized bed coating or pan coating.

Binders

In some embodiments, either the pellet cores, the intermediate coatinglayer, or both may comprise one or more binders (e.g., film formingpolymers). Suitable binders for use herein include, e.g.: alginic acidand salts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

Extended Release Coating

The pellets are coated with an extended release coating. The extendedrelease coating is adapted to delay release of the drug from the coateddrug cores for a period of time after introduction of the dosage forminto the use environment. In some embodiments, the extended releasecoating includes one or more pH-dependent or non-pH-dependent extendedrelease excipients. Examples of non-pH dependent extended releasepolymers include ethyl cellulose, hydroxypropylmethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, copolymer of ethyl acrylate, methyl methacrylate (e.g.Eudgrait RS) etc. Examples of pH dependent extended release excipientsinclude methacrylic acic copolymers, hydroxypropylmethyl celluloseacetate succinate, hydroxypropylmethyl cellulose phthalate, andcellulose acetate phthalate etc. The extended release coating may alsoinclude a pore former, such as povidone, polyethylene glycol,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, etc., sugarssuch as sucrose, mannitol, lactose, and salts, such as sodium chloride,sodium citrate, etc., a plasticizer, such as acetylated citrated esters,acetylated glycerides, castor oil, citrate esters, dibutylsebacate,glyceryl monostearate, diethyl phthalate, glycerol, medium chaintriglycerides, propylene glycol, polyethylene glycol. The extendedrelease coating may also include one or more additional excipients, suchas lubricants (e.g., magnesium stearate, talc etc.).

Extended release coating can be applied using conventional coatingtechniques such as fluidized bed coating, pan coating etc. The drugcoated pellets cores, which optionally comprise a seal coat, are coatedwith the extended release coating by fluidized bed coating.

Extended Release Excipients (Coating Polymers)

As described herein, exemplary extended release excipients include, butare not limited to, insoluble plastics, hydrophilic polymers, and fattycompounds. Plastic matrices include, but are not limited to, methylacrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.Hydrophilic polymers include, but are not limited to, cellulosicpolymers such as methyl and ethyl cellulose, hydroxyalkyl cellulosessuch as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethyl cellulose, and cross-linked acrylic acid polymers likeCarbopol® 934, polyethylene oxides and mixtures thereof. Fatty compoundsinclude, but are not limited to, various waxes such as carnauba wax andglyceryl tristearate and wax-type substances including hydrogenatedcastor oil or hydrogenated vegetable oil, or mixtures thereof.

In certain embodiments, the plastic material can be a pharmaceuticallyacceptable acrylic polymer, including but not limited to, acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymerpoly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers.

In certain other embodiments, the acrylic polymer is comprised of one ormore ammonio methacrylate copolymers Ammonio methacrylate copolymers arewell known in the art, and are described in NF XVII as fully polymerizedcopolymers of acrylic and methacrylic acid esters with a low content ofquaternary ammonium groups.

In still other embodiments, the acrylic polymer is an acrylic resinlacquer such as that which is commercially available from Rohm Pharmaunder the trade name Eudragit®. In further embodiments, the acrylicpolymer comprises a mixture of two acrylic resin lacquers commerciallyavailable from Rohm Pharma under the trade names Eudragit® RL30D andEudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D arecopolymers of acrylic and methacrylic esters with a low content ofquaternary ammonium groups, the molar ratio of ammonium groups to theremaining neutral (meth)acrylic esters being 1:20 in Eudragit RL30D and1:40 in Eudragit® RS30D. The mean molecular weight is about 150,000.Edragit® S-100 and Eudragit® L-100 are also suitable for use herein. Thecode designations RL (high permeability) and RS (low permeability) referto the permeability properties of these agents. Eudragit® RL/RS mixturesare insoluble in water and in digestive fluids. However,multiparticulate systems formed to include the same are swellable andpermeable in aqueous solutions and digestive fluids.

The polymers described above such as Eudragit® RL/RS may be mixedtogether in any desired ratio in order to ultimately obtain an extendedrelease formulation having a desirable dissolution profile. One skilledin the art will recognize that other acrylic polymers may also be used,such as, for example, Eudragit® L.

Pore Formers

In some embodiments, the extended release coating includes a poreformer. Pore formers suitable for use in the extended release coatingcan be organic or inorganic agents, and include materials that can bedissolved, extracted or leached from the coating in the environment ofuse. Examples of pore formers include but are not limited to organiccompounds such as mono-, oligo-, and polysaccharides including sucrose,glucose, fructose, mannitol, mannose, galactose, lactose, sorbitol,pullulan, dextran; polymers soluble in the environment of use such aswater-soluble hydrophilic polymers, such as povidone, crospovidone,polyethylene glycol, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyalkyl celluloses, carboxyalkyl celluloses, celluloseethers, acrylic resins, polyvinylpyrrolidone, cross-linkedpolyvinylpyrrolidone, polyethylene oxide, carbowaxes, Carbopol®, and thelike, diols, polyols, polyhydric alcohols, polyalkylene glycols,polyethylene glycols, polypropylene glycols, or block polymers thereof,polyglycols, poly(α-Ω) alkylenediols; inorganic compounds such as alkalimetal salts, lithium carbonate, sodium chloride, sodium bromide,potassium chloride, potassium sulfate, potassium phosphate, sodiumacetate, sodium citrate, suitable calcium salts, and the like. Incertain embodiments, plasticizers can also be used as a pore former.

Capsules

The extended release pellets are introduced into a suitable capsule byusing an encapsulator equipped with pellet dosing chamber. The capsulesizes may be 00, 0, 0EL, 1, 1EL, 2, 2EL, 3, 4 or 5. A particularlypreferred composition that provides ideal pharmacokinetic properties andplasma concentration profiles is a pellet-in-capsule composition thatcomprises a plurality of pellets, typically having a diameter of about500 μm to 1.2 mm, and preferably about 700 μm to 1000 μm, where eachpellet comprises a core comprising amantadine and a binder, and anextended release coating surrounding the core that extends release ofthe amantadine so as to provide the desired pharmacokinetic propertiesand amantadine plasma concentration profiles described above.

In some embodiments, the pellets in the pellet-in-capsule are in a size0 or smaller, preferably a size 1 or smaller capsule. Mean pelletdiameters in some embodiments may be in a range of 500 μm to 1200 μm,e.g. from 500 μm to 1100 μm, from 500 μm to 1000 μm, from 500 μm to 900μm, from 500 μm to 800 μm, from 500 μm to 700 μm, from 600 μm to 1100μm, from 600 μm to 1000 μm, from 600 μm to 900 μm, from 600 μm to 800μm, from 600 μm to 700 μm, from 700 μm to 1100 μm, from 700 μm to 1000μm, from 700 μm to 900 μm, or from 700 μm to 800 μm. In some embodimentsthe mean particle diameters are, ±10%, e.g.: 500 μm, 550 μm, 600 μm, 650μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950 μm, 1000 μm, 1050 μm,1100 μm, 1150 μm or 1200 μm.

One preferred composition of the invention is a pellet-in-capsulecomposition wherein each pellet comprises a core that comprises a coreseed with a mixture of amantadine and a binder coated onto the coreseed, and an extended release coating surrounding the core comprisingethyl cellulose, a pore forming agent such as hydroxypropyl methylcellulose or povidone, and a plasticizer. In some embodiments, thepellets may further comprise a seal coating between the pellet core andthe extended release coating. The pellets are formulated using methodsknown in the art, such as those described in Example 1 below. In aspecific embodiment, based on the combined weight of the pellet core andextended release coating, the amantadine is present in amounts from20-80 wt %, 45-70 wt %, 40-50 wt %, 45-55 wt %, 50-60 wt %, 55-65 wt %,60-70 wt %, 65-75 wt %, 70-80 wt %, or 40 to 60 wt %, the binder, whichis preferably hydroxypropyl methyl cellulose, copovidone, or mixturesthereof, is present in amounts from 1 to 25 wt %, the core seed,preferably a sugar sphere (nonpareil) or microcrystalline cellulose seed(e.g. Celphere®), is present in amounts from 8 to 25 wt %, the ethylcellulose is present in amounts from 10 to 20 wt %, the pore formingagent, preferably povidone, is present in amounts from 1 to 4 wt %, andthe plasticizer is present in amounts from 1 to 4 wt %. In anotherspecific embodiment, based on the combined weight of the pellet core andextended release coating, the amantadine is present in amounts from 50to 70 wt %, the binder, which is preferably hydroxypropyl methylcellulose, copovidone, or mixtures thereof, is present in amounts from 1to 25 wt %, the core seed, preferably a sugar sphere (nonpareil) ormicrocrystalline cellulose seed (e.g. Celphere®), is present in amountsfrom 5 to 15 wt %, the ethyl cellulose is present in amounts from 1 to15 wt %, the pore forming agent, preferably povidone, is present inamounts from 0.25 to 4 wt %, and the plasticizer is present in amountsfrom 0.25 to 4 wt %.

Additional embodiments of the invention are illustrated in the Table,below, entitled “Various Amantadine ER Capsule Size 1 Formulations”. Bymeans of methods and compositions described herein, formulations can bemade that achieve the desired dissolution characteristics and targetpharmacokinetic profiles described herein. More specifically,therapeutically effective doses of amantadine can be administered oncedaily in no more than two size 1 (or smaller, e.g. size 2 or 3) capsulesusing the manufacturing methods and compositions that have beendescribed herein to achieve these results. In particular, higher drugloading can be achieved using compositions and manufacturing methodsdescribed herein. In some embodiments, higher drug loading may beachieved, with the required dissolution profile, using smaller corepellet sizes and concomitantly increased drug layering on smaller cores,but with no change in the extended release coat. In some embodiments,using alternative manufacturing approaches described herein, e.g.extrusion and spheronization, even higher drug loads can be achieved torealize the desired dissolution profile, enabling high amantadine drugloads with suitable pharmacokinetic profiles, resulting in compositionsthat are therapeutically more effective, and at least as well tolerated,and can be filled in relatively small sized capsules (e.g., size 1, 2 or3), enabling ease of administration to patients.

TABLE Various Amantadine ER Capsule Size 1 Formulations Extended AMTInert Core Active Release Bulk % Fill in AMT Dissolution (%) StrengthManufacture Pellet Size Drug Coating % Density Size 1 (at T (hrs)): (mg)Method (mm) % w/w w/w (g/cm³) Capsule 2 hrs 6 hrs 12 hrs 110 mg Fluidbed coating 0.3-0.5 40-50% 10-30% 0.6-1.0 60-70% <25% 40-80% >80% 140 mgFluid bed coating 0.3-0.5 45-50% 10-30% 0.6-1.0 80-90% <25% 40-80% >80%150 mg Fluid bed coating 0.3-0.5 50-55% 10-30% 0.6-1.0 80-90% <25%40-80% >80% 170 mg Fluid bed coating 0.2-0.3 50-55% 10-30% 0.6-1.080-90% <25% 40-80% >80% 170 mg Extrusion N/A 55-75% 10-30% 0.6-1.065-75% <25% >80% spheronization, pan or fluidized bed coating 190 mgExtrusion N/A 55-75% 10-30% 0.6-1.0 75-85% <25% 40-80% >80%spheronization, pan or fluidized bed coating 210 mg Extrusion N/A 55-75%10-30% 0.6-1.0 80-90% <25% 40-80% >80% spheronization, pan or fluidizedbed coating 230 mg Extrusion N/A 55-75% 10-30% 0.6-1.0 85-95% <25%40-80% >80% spheronization, pan or fluidized bed coating

In some embodiment, the amantadine, or a pharmaceutically acceptablesalt thereof, is present in amounts from 20 to 80 wt (based on thecombined weight of the pellet core and extended release coating), with abulk density of 0.3 to 1.2 g/cm³. In some embodiments, the amantadine orpharmaceutically acceptable salt thereof is present in amounts from 20to 77.5 wt %, from 20 to 75 wt %, from 20 to 72.5 wt %, from 20 to 70 wt%, from 20 to 67.5 wt %, from 20 to 65 wt %, from 20 to 62.5 wt %, from20 to 60 wt %, from 20 to 57.5 wt %, from 20 to 55 wt %, from 20 to 52.5wt %, from 20 to 50 wt %, from 20 to 47.5 wt %, from 20 to 45 wt %, from20 to 42.5 wt %, from 20 to 40 wt %, from 20 to 37.5 wt %, from 20 to 35wt %, from 20 to 32.5 wt %, from 20 to 30 wt %, from 30 to 80 wt %, from30 to 77.5 wt %, from 30 to 75 wt %, from 30 to 72.5 wt %, from 30 to 70wt %, from 30 to 67.5 wt %, from 30 to 65 wt %, from 30 to 62.5 wt %,from 30 to 60 wt %, from 30 to 57.5 wt %, from 30 to 55 wt %, from 30 to52.5 wt %, from 30 to 50 wt %, from 30 to 47.5 wt %, from 30 to 45 wt %,from 30 to 42.5 wt %, from 30 to 40 wt %, from 40 to 80 wt %, from 40 to77.5 wt %, from 40 to 75 wt %, from 40 to 72.5 wt %, from 40 to 70 wt %,from 40 to 67.5 wt %, from 40 to 65 wt %, from 40 to 62.5 wt %, from 40to 60 wt %, from 40 to 57.5 wt %, from 40 to 55 wt %, from 40 to 52.5 wt%, from 40 to 50 wt %, from 40 to 47.5 wt %, from 40 to 45 wt %, from 50to 80 wt %, from 50 to 77.5 wt %, from 50 to 75 wt %, from 50 to 72.5 wt%, from 50 to 70 wt %, from 50 to 67.5 wt %, from 50 to 65 wt %, from 50to 62.5 wt %, from 50 to 60 wt %, from 50 to 57.5 wt %, from 50 to 55 wt%, from 60 to 80 wt %, from 60 to 77.5 wt %, from 60 to 75 wt %, from 60to 72.5 wt %, from 60 to 70 wt %, from 60 to 67.5 wt %, from 60 to 65 wt%. In some embodiments, the bulk density is 0.3 to 1.2 g/cm³, 0.3 to1.15 g/cm³, 0.3 to 1.1 g/cm³, 0.3 to 1.05 g/cm³, 0.3 to 1.0 g/cm³, 0.3to 0.9 g/cm³, 0.3 to 0.8 g/cm³, 0.3 to 0.7 g/cm³, 0.3 to 0.6 g/cm³, 0.3to 0.5 g/cm³, 0.3 to 0.4 g/cm³, 0.4 to 1.2 g/cm³, 0.4 to 1.15 g/cm³, 0.4to 1.1 g/cm³, 0.4 to 1.05 g/cm³, 0.4 to 1.0 g/cm³, 0.4 to 0.9 g/cm³, 0.4to 0.8 g/cm³, 0.4 to 0.7 g/cm³, 0.4 to 0.6 g/cm³, 0.4 to 0.5 g/cm³, 0.5to 1.2 g/cm³, 0.5 to 1.15 g/cm³, 0.5 to 1.1 g/cm³, 0.5 to 1.05 g/cm³,0.5 to 1.0 g/cm³, 0.5 to 0.9 g/cm³, 0.5 to 0.8 g/cm³, 0.5 to 0.7 g/cm³,0.5 to 0.6 g/cm³, 0.6 to 1.2 g/cm³, 0.6 to 1.15 g/cm³, 0.6 to 1.1 g/cm³,0.6 to 1.05 g/cm³, 0.6 to 1.0 g/cm³, 0.6 to 0.9 g/cm³, 0.6 to 0.8 g/cm³,0.6 to 0.7 g/cm³, 0.7 to 1.2 g/cm³, 0.7 to 1.15 g/cm³, 0.7 to 1.1 g/cm³,0.7 to 1.05 g/cm³, 0.7 to 1.0 g/cm³, 0.7 to 0.9 g/cm³, 0.7 to 0.8 g/cm³,0.5 to 1.2 g/cm³, 0.8 to 1.15 g/cm³, 0.8 to 1.1 g/cm³, 0.8 to 1.05g/cm³, 0.8 to 1.0 g/cm³, 0.8 to 0.9 g/cm³, 0.9 to 1.2 g/cm³, 0.9 to 1.15g/cm³, 0.9 to 1.1 g/cm³, 0.9 to 1.05 g/cm³, or 0.9 to 1.0 g/cm³. In someembodiments, the composition is in a dosage unit comprising a pellet incapsule formulation, wherein the capsule size is size 00, size 0, size1, size 2 or size 3. In some preferred embodiments, the dosage unitincludes pellets containing from 50 to 250 mg of amantadine in a size 0,1, 2 or 3 capsule. In some embodiments, the dosage unit includes pelletscontaining from 100 to 250 mg, e.g. 100 to 200 mg of amantadine in asize 0, 1, 2 or 3 capsule, preferably a size 1, 2 or 3 capsule. In amore specific embodiment, the dosage unit comprises about 110, 120, 130,140, 150, 160 170, 180, 190, 210, or 220 mg amantadine, or apharmaceutically acceptable salt thereof. In another more specificembodiment, the dosage unit comprises 110 mg amantadine hydrochloride.In another more specific embodiment, the dosage unit comprises 130 mgamantadine hydrochloride. In another more specific embodiment, thedosage unit comprises 170 mg amantadine hydrochloride. In another morespecific embodiment, the dosage unit comprises 210 mg amantadinehydrochloride.

Suitable plasticizers include medium chain triglycerides, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, castor oil, and the like. The pellets are filled intocapsules to provide the desired strength of amantadine. An advantage ofthis composition is it provides the desired release properties that makethe composition suitable for administration during said period beforebedtime. A further advantage is that the extended release coating issufficiently durable so that the capsule can be opened and the pelletssprinkled onto food for administration to patients who have difficultyswallowing pills, without adversely affecting the release properties ofthe composition. When the composition is administered by sprinkling ontofood, it is preferred to use a soft food such as applesauce or chocolatepudding, which is consumed within 30 minutes, and preferably within 15minutes. A yet further advantage of the above-described composition isthat it has very good batch-to-batch reproducibility and shelf-lifestability.

In some embodiments, the composition of the invention has an in vitrodissolution profile of amantadine of not more than 25% at 2 hours,55-85% at 6 hours, and at least 80% at 12 hours, as measured using a USPApparatus II (Paddles) at 50 rpm with 500 ml water at 37° C. as thedissolution medium. More preferably, the in vitro dissolution is furthercharacterized by release of amantadine of not more than 10% at 1 hour,30-50% at 4 hours, and at least 90% at 12 hours.

In additional embodiments, 110 mg to 210 mg of ER amantadine in a size 1capsule of the composition of the invention has an in vitro dissolutionprofile of amantadine of not more than 25% at 2 hours, 55-85% at 6hours, and at least 80% at 12 hours, as measured using a USP ApparatusII (Paddles) at 50 rpm with 500 ml water at 37° C. as the dissolutionmedium. More preferably, the in vitro dissolution is furthercharacterized by release of amantadine of not more than 10% at 1 hour,30-50% at 4 hours, and at least 90% at 12 hours.

In one embodiment of any of the above aspects the composition has an invitro dissolution profile of amantadine which shows at least one of (i)not more than 25% dissolution at 2 hours, (ii) not more than 25-55%dissolution at 6 hours, and (iii) at least 80% dissolution at 12 hours,using a USP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37° C.as the dissolution medium. In a more specific embodiment two of criteria(i), (ii) and (iii) are met. In a more specific embodiment, all three ofcriteria (i), (ii) and (iii) are met.

In one embodiment of any of the above aspects the composition has an invitro dissolution profile of amantadine which shows at least one of (i)not more than 20% dissolution at 1 hour, (ii) about 25-45% dissolutionat 2 hours, (iii) not more than 50-80% dissolution at 4 hours, and (iii)at least 80% dissolution at 8 hours, using a USP Apparatus II (Paddles)at 50 rpm with 500 ml water at 37° C. as the dissolution medium. In amore specific embodiment two of criteria (i), (ii) and (iii) are met. Ina more specific embodiment, all three of criteria (i), (ii) and (iii)are met.

A preferred pellet-in-capsule compostion of the invention, in additionto having the above in vitro dissolution properties and any of theabove-described pharmacokinetic properties (e.g. in vivo releaseprofile, Tmax, Cmax/Cmin ratio, etc) that make the composition suitablefor administration in said period before bedtime. The composition isfurther characterized by providing a Cmax of 1.6-2.4 ng/ml per mg ofamantadine and an AUC_(0-inf) of 40-75 ng*h/mL per mg of amantadineafter oral administration of a single dose of the capsule to a humansubject in a fasted state. A preferred pellet-in-capsule composition isfurther characterized by a steady state plasma concentration in whichonce daily oral administration of the capsule to a human subjectprovides a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine, a Cmin of 1.1to 2.6 ng/ml per mg of amantadine, and an AUC₀₋₂₄ of 48-73 ng*h/mL permg of amantadine.

The above-described pellet-in-capsule compositions may be provided at astrength suitable for amantadine therapy. Typical strengths range fromat least about 50 mg to about 250 mg. In a specific embodiment, thecapsule strength is 70 mg, 80 mg, 90 mg, 110 mg, 120 mg, 125 mg, 130 mg,140 mg, 150 mg, 160 mg, 160 mg, 170 mg, 180 mg, 190 mg, 210 mg, and 220mg, that provides a single dose AUC_(0-inf) per mg that is equivalent toa 100 mg tablet of an immediate release formulation of amantadine HCl(e.g. Symmetrel®, or other FDA Orange Book reference listed drug). One,two, or three, of such capsules can be administered to a subject in theperiod before bedtime. In a preferred embodiment, between 220 mg and 650mg of amantadine is adminstered using 2 capsules of a suitable ERformulations once daily.

The invention may also be described in terms of the following numberedembodiments:

-   1. An extended release (ER) composition comprising amantadine, or a    pharmaceutically acceptable salt thereof, for use in a method of    administering amantadine to a subject in need thereof, said method    comprising orally administering said composition less than three    hours before bedtime (i.e. the time at which the subject wishes to    go to sleep for the night).-   2. Use of amantadine, or a pharmaceutically acceptable salt thereof,    in the manufacture of a medicament for the treatment of a disease    mediated by the NMDA receptor to a subject in need thereof, said    medicament being an extended release (ER) composition, and said    treatment comprising orally administering said composition less than    three hours before bedtime (i.e. the time at which the subject    wishes to go to sleep for the night).-   3. An extended release (ER) composition comprising amantadine, or a    pharmaceutically acceptable salt thereof, for use in a method of    reducing sleep disturbance in a human subject undergoing treatment    with amantadine, said method comprising administering said    composition less than three hours before bedtime (i.e. the time at    which the subject wishes to go to sleep for the night).-   4. Use of amantadine, or a pharmaceutically acceptable salt thereof,    in the manufacture of a medicament for reducing sleep disturbance in    a human subject undergoing treatment with amantadine, said    medicament being an extended release (ER) composition and being    adapted for administration less than three hours before bedtime    (i.e. the time at which the subject wishes to go to sleep for the    night).-   5. The use or composition of any one of embodiments 1-4 wherein    administration occurs less than 1 hour before bedtime.-   6. The use or composition of any one of embodiments 1-5, wherein the    patient has been diagnosed with Parkinson's disease.-   7. The use or composition of any one of embodiments 1-6, wherein the    composition is administered once daily.-   8. The use or composition of any one of embodiments 1-7, wherein the    composition is added to food prior to administration.-   9. The use or composition of any one of embodiments 1-8, wherein    there is no increase in plasma concentration of amantadine for at    least one hour after the administration at steady state.-   10. The use or composition of any one of embodiments 1-9, wherein    there is no increase in plasma concentration of amantadine for at    least two hours after the administration at steady state.-   11. The use of composition of any one of embodiments 1-10, wherein,    the amantadine has a single dose Tmax of 9 to 15 hours and/or a    steady state Tmax of 7 to 13 hours after administration.-   12. The use or composition of any one of embodiments 1-11, wherein    the amantadine has a single dose Tmax of 10 to 14 hours after    administration, and/or a steady state Tmax of 8 to 12 hours after    administration.-   13. The use of composition of any one of embodiments 1-10, wherein,    the amantadine has a single dose Tmax of 9 to 15 hours, and/or a    steady state Tmax of 7 to 13 hours after administration.-   14. The use or composition of any one of embodiments 1-11, wherein    the amantadine has a single dose Tmax of 10 to 14 hours after    administration, and/or a steady state Tmax of 8 to 12 hours after    administration.-   15. The use of composition of any one of embodiments 1-10, wherein,    the amantadine has a single dose Tmax of 9 to 15 hours, and/or a    steady state Tmax of 7 to 13 hours after administration.-   16. The use or composition of any one of embodiments 1-11, wherein    the amantadine has a single dose Tmax of 10 to 14 hours after    administration, and/or a steady state Tmax of 8 to 12 hours after    administration.-   17. The use or composition of any one of embodiments 1-12, wherein    the amantadine has a single dose Tmax of 11 to 13 hours after    administration, and or a steady state Tmax of 9 to 11 hours after    administration.-   18. The use or composition of any one of embodiments 1-13, wherein a    once daily oral administration of the composition to a human subject    provides a steady state plasma concentration profile characterized    by a concentration increase of amantadine of less than 25% at three    hours after the administration.-   19. The use or composition of any one of embodiments 1-14 having a    Cmax/Cmin ratio of 1.5 to 2.0.-   20. The use or composition of any one of embodiments 1-15 having a    Cmax/Cmin ratio of 1.7 to 1.9.-   21. The use or composition of any one of embodiments 1-16, wherein    the amantadine is amantadine hydrochloride or amantadine sulfate.-   22. The use or composition of any one of embodiments 1-17 wherein    the composition comprises 50 to 600 mg of amantadine, or a    pharmaceutically acceptable salt thereof.-   23. The use or composition of embodiment 18, wherein the composition    is administered as one, two, or three or four unit dosage forms each    comprising 100 to 175 mg amantadine, or a pharmaceutically    acceptable salt thereof.-   24. The use or composition of any one of embodiments 1-19 wherein    the composition comprises 200 to 420 mg of amantadine, or a    pharmaceutically acceptable salt thereof.-   25. The use or composition of embodiment 20, wherein the composition    is administered as two unit dosage forms each comprising 110 to 175    mg amantadine, or a pharmaceutically acceptable salt thereof.-   26. The use or composition of any one of embodiments 1 to 17,    wherein the composition comprises 50 to 200 mg amantadine or a    pharmaceutically acceptable salt thereof.-   27. The use or composition of embodiment 22, wherein the composition    comprises 100 to 125 mg amantadine, or a pharmaceutically acceptable    salt thereof.-   28. The use or composition of embodiment 23, wherein the composition    comprises 110 mg amantadine hydrochloride.-   29. The use or composition of any one of embodiments 1-24, wherein    oral administration of a single dose of the composition to a human    subject in a fasted state provides a maximum plasma concentration    (Cmax) of amantadine of 1.6 to 2.4 ng/ml per mg of amantadine and an    AUC_(0-inf) of 40 to 75 ng*h/mL per mg of amantadine.-   30. The use or composition of any one of embodiments 1-25, wherein    once daily oral administration of a dose of the composition to a    human subject provides a steady state plasma amantadine    concentration profile characterized by:    -   (i) a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine,    -   (ii) a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine, and    -   (iii) an AUC₀₋₂₄ of 44 to 83 ng*h/mL per mg of amantadine.-   31. The use or composition of embodiment 26, wherein the steady    state plasma concentration profile is further characterized by:    -   (iv) no increase in plasma concentration of amantadine for at        least one hour after the administration; and    -   (v) a Cmax/Cmin ratio of 1.5 to 2.0.-   32. The use or composition of embodiment 27, wherein the steady    state plasma concentration profile is further characterized by:    -   (iv) no increase in concentration of amantadine for at least two        hours after the administration; and    -   (v) a Cmax/Cmin ratio of 1.7 to 1.9.-   33. The use or composition of any one of embodiments 1-28, wherein    the composition has an in vitro dissolution profile of amantadine of    not more than 25% at 2 hours, 55-85% at 6 hours, and at least 80% at    12 hours, using a USP Apparatus II (Paddles) at 50 rpm with 500 ml    water at 37° C. as the dissolution medium.-   34. The use or composition of embodiment 29, wherein the in vitro    dissolution profile of amantadine is further characterized by    release of amantadine of not more than 10% at 1 hour, 30-50% at 4    hours, and at least 90% at 12 hours-   35. The use or composition of any one of embodiments 1-30, wherein    the composition has an AUC profile after administration of a single    dose of the composition characterized by: a fractional AUC from 0 to    4 hours that is less than 5% of AUC_(0-inf); a fractional AUC from 0    to 8 hours that is about 5 to 15% of AUC_(0-inf); a fractional AUC    from 0 to 12 hours that is about 10 to 40% of AUC_(0-inf); a    fractional AUC from 0 to 18 hours that is about 25 to 60% of    AUC_(0-inf); and a fractional AUC from 0 to 24 hours that is about    40 to 75% of AUC_(0-inf)-   36. The use or composition of any one of embodiments 1-31, wherein    the composition has an AUC profile after once daily dosing of the    composition at steady state conditions characterized by: a    fractional AUC from 0 to 4 hours that is about 2 to 25% of AUC₂₄; a    fractional AUC from 0 to 8 hours that is about 15 to 50% of AUC₂₄; a    fractional AUC from 0 to 12 hours that is about 30 to 70% of AUC₂₄:    and a fractional AUC from 0 to 18 hours that is about 60 to 95% of    AUC₂₄.-   37. A pharmaceutical composition as embodied in any one of    embodiments 1, 3, or 5 to 32, or the use of any one of embodiments    2, 4 or 5 to 32, wherein said composition is for oral administration    and comprises a capsule for oral administration, said capsule    comprising a plurality of pellets, each pellet comprising:    -   (a) a pellet core comprising amantadine, or a pharmaceutically        acceptable salt thereof, and    -   (b) an extended release coating surrounding the pellet core.-   38. The use or composition of embodiment 32, wherein the extended    release coating comprises ethyl cellulose, at least one of povidone    and hydroxypropyl methyl cellulose, and a plasticizer.-   39. The use or composition of any one of embodiments 33 or 34,    wherein the pellet core comprises amantadine, or a pharmaceutically    acceptable salt thereof, and a binder coated onto a core seed.-   40. The use or composition of embodiment 35, wherein, based on the    combined weight of the pellet core and extended release coating, the    amantadine is present in amounts from 40 to 60 wt %, the binder is    present in amounts from 8 to 25 wt %, the core seed is present in    amounts from 8 to 25 wt %, the ethyl cellulose is present in amounts    from 10 to 20 wt %, the povidone is present in amounts from 1 to 4    wt %, and the plasticizer is present in amounts from 1 to 4 wt %.-   41. The use or composition of any one of embodiments 33 to 36,    further comprising a seal coating between the pellet core and the    extended release coating.-   42. The use or composition of any one of embodiments 35 to 37,    wherein the wherein the pellet core comprises a binder, selected    from the group consisting of hydroxypropyl methyl cellulose,    copovidone, and mixtures thereof.-   43. The use or composition of any one of embodiments 18 to 38,    wherein the plasticizer is selected from the group consisting of    medium chain triglycerides, diethyl phthalate, citrate esters,    polyethylene glycol, glycerol, acetylated glycerides and castor oil.-   44. A composition of any one of embodiments 33 to 39, for use in a    method of treating Parkinson's disease in a human subject in need    thereof, said method comprising orally administering said    composition.

Some embodiments herein provide a method of administering amantadine toa subject in need thereof, said method comprising orally administeringan extended release (ER) composition comprising amantadine, or apharmaceutically acceptable salt thereof, less than three hours beforebedtime. In some embodiments, administration occurs less than 1 hourbefore bedtime. In some embodiments, the patient has been diagnosed withParkinson's disease. In some embodiments, the composition isadministered once daily. In some embodiments, the composition is addedto food prior to administration. In some embodiments, there is noincrease in plasma concentration of amantadine for at least one hourafter the administration. In some embodiments, there is no increase inplasma concentration of amantadine for at least two hours after theadministration. In some embodiments, the amantadine has a single doseTmax of 9 to 15 hours, and/or a steady state Tmax of 7 to 13 hours. Insome embodiments, the amantadine has a single dose Tmax of 10 to 14hours after administration, and/or a steady state Tmax of 8 to 12 hours.In some embodiments, the amantadine has a single dose Tmax of 11 to 13hours after administration, and/or a steady state Tmax of 9 to 11 hours.In some embodiments, a once daily oral administration of the compositionto a human subject provides a steady state plasma concentration profilecharacterized by a concentration increase of amantadine of less than 25%at three hours after the administration. In some embodiments, the PKcurve has a Cmax/Cmin ratio of 1.5 to 2.0. In some embodiments, the PKcurve has a Cmax/Cmin ratio of 1.7 to 1.9. In some embodiments, theratio of C-ave-day/C-ave night at steady state is 1.2 to 1.6. In someembodiments, the ratio of C-ave-morning/C-ave night at steady state is1.3 to 1.5. In some embodiments, the average amantadine plasmaconcentration during the day (C-ave-day) at steady state is 500-2000ng/ml. In some embodiments, the average amantadine plasma concentrationin the morning (C-ave-morning) at steady state is 500-2000 ng/ml. Insome embodiments, the amantadine is amantadine hydrochloride oramantadine sulfate. In some embodiments, the composition comprises 50 to600 mg of amantadine, or a pharmaceutically acceptable salt thereof. Insome embodiments, the composition is administered as one, two, or threeor four unit dosage forms each comprising 100 to 175 mg amantadine, or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition is administered as one or two unit dosage forms eachcomprising 130 to 210 mg of extended release amantadine, or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition is within a capsule of capsule size #1. In some embodiments,the composition comprises 200 to 350 mg of amantadine, or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition is administered as two unit dosage forms each comprising 100to 175 mg amantadine, or a pharmaceutically acceptable salt thereof. Insome embodiments, the composition comprises 50 to 200 mg amantadine or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises 100 to 125 mg amantadine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprises110 mg amantadine hydrochloride. In some embodiments, oraladministration of a single dose of the composition to a human subject ina fasted state provides a maximum plasma concentration (Cmax) of 1.6 to2.4 ng/ml per mg of amantadine, and an AUC_(0-inf) of 40 to 75 ng*h/mLper mg of amantadine. In some embodiments, once daily oraladministration of a dose of the composition to a human subject providesa steady state plasma concentration profile characterized by: (a) a Cmaxof 2.4 to 4.2 ng/ml per mg of amantadine; (b) a Cmin of 1.1 to 2.6 ng/mlper mg of amantadine, and (c) an AUC₀₋₂₄ of 44 to 83 ng*h/mL per mg ofamantadine. In some embodiments, the steady state plasma concentrationprofile is further characterized by: (d) no increase in plasmaconcentration of amantadine for at least one hour after theadministration; and (e) a Cmax/Cmin ratio of 1.5 to 2.0. In someembodiments, the steady state plasma concentration profile is furthercharacterized by: (f) no increase in concentration of amantadine for atleast two hours after the administration; and (g) a Cmax/Cmin ratio of1.7 to 1.9. In some embodiments, the composition has an in vitrodissolution profile of amantadine of not more than 25% at 2 hours,55-85% at 6 hours, and at least 80% at 12 hours, using a USP ApparatusII (Paddles) at 50 rpm with 500 ml water at 37° C. as the dissolutionmedium. In some embodiments, the composition has an in vitro dissolutionprofile of amantadine of not more than 25% at 2 hours, 25-55% at 6hours, and at least 80% at 12 hours, using a USP Apparatus II (Paddles)at 50 rpm with 500 ml water at 37° C. as the dissolution medium. In someembodiments, the composition has an in vitro dissolution profile ofamantadine of not more than 20% at 1 hour, 25-45% at 2 hours, 50-80% at4 hours, and at least 80% at 8 hours, using a USP Apparatus II (Paddles)at 50 rpm with 500 ml water at 37° C. as the dissolution medium. In someembodiments, the in vitro dissolution profile of amantadine is furthercharacterized by release of amantadine of not more than 10% at 1 hour,30-50% at 4 hours, and at least 90% at 12 hours. In some embodiments,the composition has an AUC profile after administration of a single doseof the composition characterized by: a fractional AUC from 0 to 4 hoursthat is less than 5% of AUC_(0-inf); a fractional AUC from 0 to 8 hoursthat is about 5 to 15% of AUC_(0-inf); a fractional AUC from 0 to 12hours that is about 10 to 40% of AUC_(0-inf); a fractional AUC from 0 to18 hours that is about 25 to 60% of AUC_(0-inf); and a fractional AUCfrom 0 to 24 hours that is about 40 to 75% of AUC_(0-inf). In someembodiments, the composition has an AUC profile after once daily dosingof the composition at steady state conditions characterized by: afractional AUC from 0 to 4 hours that is about 2 to 25% of AUC₂₄; afractional AUC from 0 to 8 hours that is about 15 to 50% of AUC₂₄; afractional AUC from 0 to 12 hours that is about 30 to 70% of AUC₂₄: anda fractional AUC from 0 to 18 hours that is about 60 to 95% of AUC₂₄.

Some embodiments herein provide a method of reducing sleep disturbancein a human subject undergoing treatment with amantadine, said methodcomprising administering an extended release (ER) composition comprisingamantadine, or a pharmaceutically acceptable salt thereof, less thanthree hours before bedtime. In some embodiments, administration occursless than 1 hour before bedtime. In some embodiments, the patient hasbeen diagnosed with Parkinson's disease. In some embodiments, thecomposition is administered once daily. In some embodiments, thecomposition is added to food prior to administration. In someembodiments, there is no increase in plasma concentration of amantadinefor at least one hour after the administration. In some embodiments,there is no increase in plasma concentration of amantadine for at leasttwo hours after the administration. In some embodiments, the amantadinehas a single dose Tmax of 9 to 15 hours, and/or a steady state Tmax of 7to 13 hours. In some embodiments, the amantadine has a single dose Tmaxof 10 to 14 hours after administration, and/or a steady state Tmax of 8to 12 hours. In some embodiments, the amantadine has a single dose Tmaxof 11 to 13 hours after administration, and/or a steady state Tmax of 9to 11 hours. In some embodiments, a once daily oral administration ofthe composition to a human subject provides a steady state plasmaconcentration profile characterized by a concentration increase ofamantadine of less than 25% at three hours after the administration. Insome embodiments, the PK curve has a Cmax/Cmin ratio of 1.5 to 2.0. Insome embodiments, the PK curve has a Cmax/Cmin ratio of 1.7 to 1.9. Insome embodiments, the ratio of C-ave-day/C-ave night at steady state is1.2 to 1.6. In some embodiments, the ratio of C-ave-morning/C-ave nightat steady state is 1.3 to 1.5. In some embodiments, the averageamantadine plasma concentration during the day (C-ave-day) at steadystate is 500-2000 ng/ml. In some embodiments, the average amantadineplasma concentration in the morning (C-ave-morning) at steady state is500-2000 ng/ml. In some embodiments, the amantadine is amantadinehydrochloride or amantadine sulfate. In some embodiments, thecomposition comprises 50 to 600 mg of amantadine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition isadministered as one, two, or three or four unit dosage forms eachcomprising 100 to 175 mg amantadine, or a pharmaceutically acceptablesalt thereof. In some embodiments, the composition is administered asone or two unit dosage forms each comprising 130 to 210 mg of extendedrelease amantadine, or a pharmaceutically acceptable salt thereof. Insome embodiments, the composition is within a capsule of capsule size#1. In some embodiments, the composition comprises 200 to 350 mg ofamantadine, or a pharmaceutically acceptable salt thereof. In someembodiments, the composition is administered as two unit dosage formseach comprising 100 to 175 mg amantadine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprises50 to 200 mg amantadine or a pharmaceutically acceptable salt thereof.In some embodiments, the composition comprises 100 to 125 mg amantadine,or a pharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises 110 mg amantadine hydrochloride. In someembodiments, oral administration of a single dose of the composition toa human subject in a fasted state provides a maximum plasmaconcentration (Cmax) of 1.6 to 2.4 ng/ml per mg of amantadine, and anAUC_(0-inf) of 40 to 75 ng*h/mL per mg of amantadine. In someembodiments, once daily oral administration of a dose of the compositionto a human subject provides a steady state plasma concentration profilecharacterized by: (a) a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine;(b) a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine, and (c) an AUC₀₋₂₄of 44 to 83 ng*h/mL per mg of amantadine. In some embodiments, thesteady state plasma concentration profile is further characterized by:(d) no increase in plasma concentration of amantadine for at least onehour after the administration; and (e) a Cmax/Cmin ratio of 1.5 to 2.0.In some embodiments, the steady state plasma concentration profile isfurther characterized by: (f) no increase in concentration of amantadinefor at least two hours after the administration; and (g) a Cmax/Cminratio of 1.7 to 1.9. In some embodiments, the composition has an invitro dissolution profile of amantadine of not more than 25% at 2 hours,55-85% at 6 hours, and at least 80% at 12 hours, using a USP ApparatusII (Paddles) at 50 rpm with 500 ml water at 37° C. as the dissolutionmedium. In some embodiments, the composition has an in vitro dissolutionprofile of amantadine of not more than 25% at 2 hours, 25-55% at 6hours, and at least 80% at 12 hours, using a USP Apparatus II (Paddles)at 50 rpm with 500 ml water at 37° C. as the dissolution medium. In someembodiments, the composition has an in vitro dissolution profile ofamantadine of not more than 20% at 1 hour, 25-45% at 2 hours, 50-80% at4 hours, and at least 80% at 8 hours, using a USP Apparatus II (Paddles)at 50 rpm with 500 ml water at 37° C. as the dissolution medium. In someembodiments, the in vitro dissolution profile of amantadine is furthercharacterized by release of amantadine of not more than 10% at 1 hour,30-50% at 4 hours, and at least 90% at 12 hours. In some embodiments,the composition has an AUC profile after administration of a single doseof the composition characterized by: a fractional AUC from 0 to 4 hoursthat is less than 5% of AUC_(0-inf); a fractional AUC from 0 to 8 hoursthat is about 5 to 15% of AUC_(0-inf); a fractional AUC from 0 to 12hours that is about 10 to 40% of AUC_(0-inf); a fractional AUC from 0 to18 hours that is about 25 to 60% of AUC_(0-inf); and a fractional AUCfrom 0 to 24 hours that is about 40 to 75% of AUC_(0-inf). In someembodiments, the composition has an AUC profile after once daily dosingof the composition at steady state conditions characterized by: afractional AUC from 0 to 4 hours that is about 2 to 25% of AUC₂₄; afractional AUC from 0 to 8 hours that is about 15 to 50% of AUC₂₄; afractional AUC from 0 to 12 hours that is about 30 to 70% of AUC₂₄: anda fractional AUC from 0 to 18 hours that is about 60 to 95% of AUC₂₄.

Some embodiments herein provide a method of treating levodopa induceddyskinesia in a patient with Parkinson's disease, said method comprisingorally administering once daily an extended release (ER) compositioncomprising amantadine, or a pharmaceutically acceptable salt thereof,less than about three hours before bedtime. In some embodiments,administration occurs less than 1 hour before bedtime. In someembodiments, the patient has been diagnosed with Parkinson's disease. Insome embodiments, the composition is administered once daily. In someembodiments, the composition is added to food prior to administration.In some embodiments, there is no increase in plasma concentration ofamantadine for at least one hour after the administration. In someembodiments, there is no increase in plasma concentration of amantadinefor at least two hours after the administration. In some embodiments,the amantadine has a single dose Tmax of 9 to 15 hours, and/or a steadystate Tmax of 7 to 13 hours. In some embodiments, the amantadine has asingle dose Tmax of 10 to 14 hours after administration, and/or a steadystate Tmax of 8 to 12 hours. In some embodiments, the amantadine has asingle dose Tmax of 11 to 13 hours after administration, and/or a steadystate Tmax of 9 to 11 hours. In some embodiments, a once daily oraladministration of the composition to a human subject provides a steadystate plasma concentration profile characterized by a concentrationincrease of amantadine of less than 25% at three hours after theadministration. In some embodiments, the PK curve has a Cmax/Cmin ratioof 1.5 to 2.0. In some embodiments, the PK curve has a Cmax/Cmin ratioof 1.7 to 1.9. In some embodiments, the ratio of C-ave-day/C-ave nightat steady state is 1.2 to 1.6. In some embodiments, the ratio ofC-ave-morning/C-ave night at steady state is 1.3 to 1.5. In someembodiments, the average amantadine plasma concentration during the day(C-ave-day) at steady state is 500-2000 ng/ml. In some embodiments, theaverage amantadine plasma concentration in the morning (C-ave-morning)at steady state is 500-2000 ng/ml. In some embodiments, the amantadineis amantadine hydrochloride or amantadine sulfate. In some embodiments,the composition comprises 50 to 600 mg of amantadine, or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition is administered as one, two, or three or four unit dosageforms each comprising 100 to 175 mg amantadine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition isadministered as one or two unit dosage forms each comprising 130 to 210mg of extended release amantadine, or a pharmaceutically acceptable saltthereof. In some embodiments, the composition is within a capsule ofcapsule size #1. In some embodiments, the composition comprises 200 to350 mg of amantadine, or a pharmaceutically acceptable salt thereof. Insome embodiments, the composition is administered as two unit dosageforms each comprising 100 to 175 mg amantadine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprises50 to 200 mg amantadine or a pharmaceutically acceptable salt thereof.In some embodiments, the composition comprises 100 to 125 mg amantadine,or a pharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises 110 mg amantadine hydrochloride. In someembodiments, oral administration of a single dose of the composition toa human subject in a fasted state provides a maximum plasmaconcentration (Cmax) of 1.6 to 2.4 ng/ml per mg of amantadine, and anAUC_(0-inf) of 40 to 75 ng*h/mL per mg of amantadine. In someembodiments, once daily oral administration of a dose of the compositionto a human subject provides a steady state plasma concentration profilecharacterized by: (a) a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine;(b) a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine, and (c) an AUC₀₋₂₄of 44 to 83 ng*h/mL per mg of amantadine. In some embodiments, thesteady state plasma concentration profile is further characterized by:(d) no increase in plasma concentration of amantadine for at least onehour after the administration; and (e) a Cmax/Cmin ratio of 1.5 to 2.0.In some embodiments, the steady state plasma concentration profile isfurther characterized by: (f) no increase in concentration of amantadinefor at least two hours after the administration; and (g) a Cmax/Cminratio of 1.7 to 1.9. In some embodiments, the composition has an invitro dissolution profile of amantadine of not more than 25% at 2 hours,55-85% at 6 hours, and at least 80% at 12 hours, using a USP ApparatusII (Paddles) at 50 rpm with 500 ml water at 37° C. as the dissolutionmedium. In some embodiments, the composition has an in vitro dissolutionprofile of amantadine of not more than 25% at 2 hours, 25-55% at 6hours, and at least 80% at 12 hours, using a USP Apparatus II (Paddles)at 50 rpm with 500 ml water at 37° C. as the dissolution medium. In someembodiments, the composition has an in vitro dissolution profile ofamantadine of not more than 20% at 1 hour, 25-45% at 2 hours, 50-80% at4 hours, and at least 80% at 8 hours, using a USP Apparatus II (Paddles)at 50 rpm with 500 ml water at 37° C. as the dissolution medium. In someembodiments, the in vitro dissolution profile of amantadine is furthercharacterized by release of amantadine of not more than 10% at 1 hour,30-50% at 4 hours, and at least 90% at 12 hours. In some embodiments,the composition has an AUC profile after administration of a single doseof the composition characterized by: a fractional AUC from 0 to 4 hoursthat is less than 5% of AUC_(0-inf); a fractional AUC from 0 to 8 hoursthat is about 5 to 15% of AUC_(0-inf); a fractional AUC from 0 to 12hours that is about 10 to 40% of AUC_(0-inf); a fractional AUC from 0 to18 hours that is about 25 to 60% of AUC_(0-inf); and a fractional AUCfrom 0 to 24 hours that is about 40 to 75% of AUC_(0-inf). In someembodiments, the composition has an AUC profile after once daily dosingof the composition at steady state conditions characterized by: afractional AUC from 0 to 4 hours that is about 2 to 25% of AUC₂₄; afractional AUC from 0 to 8 hours that is about 15 to 50% of AUC₂₄; afractional AUC from 0 to 12 hours that is about 30 to 70% of AUC₂₄: anda fractional AUC from 0 to 18 hours that is about 60 to 95% of AUC₂₄.

Some embodiments herein provide a pharmaceutical composition for any ofthe methods described herein, wherein said composition is for oraladministration and comprises a capsule for oral administration, saidcapsule comprising a plurality of pellets, each pellet comprising: (a) apellet core comprising amantadine, or a pharmaceutically acceptable saltthereof, and (b) an extended release coating surrounding the pelletcore. In some embodiments, the extended release coating comprises ethylcellulose, at least one of povidone and hydroxypropyl methyl cellulose,and a plasticizer. In some embodiments, the pellet core comprisesamantadine, or a pharmaceutically acceptable salt thereof, and a bindercoated onto a core seed. In some embodiments, based on the combinedweight of the pellet core and extended release coating, the amantadineis present in amounts from 40 to 60 wt %, the binder is present inamounts from 8 to 25 wt %, the core seed is present in amounts from 1 to25 wt %, the ethyl cellulose is present in amounts from 10 to 20 wt %,the povidone is present in amounts from 1 to 4 wt %, and the plasticizeris present in amounts from 1 to 4 wt %. In some embodiments, thecomposition further comprises a seal coating between the pellet core andthe extended release coating. In some embodiments, the pellet corecomprises a binder selected from the group consisting of hydroxypropylmethyl cellulose, copovidone, and mixtures thereof. In some embodiments,the plasticizer is selected from the group consisting of medium chaintriglycerides, diethyl phthalate, citrate esters, polyethylene glycol,glycerol, acetylated glycerides and castor oil.

Some embodiments herein provide a method of administering amantadine, ora pharmaceutically acceptable salt thereof, to a human subject in needthereof, said method comprising orally administering a pharmaceuticalcomposition comprising amantadine in a capsule for oral administration,said capsule comprising a plurality of pellets, each pellet comprising:(a) a pellet core comprising amantadine, or a pharmaceuticallyacceptable salt thereof, and (b) an extended release coating surroundingthe pellet core. In some embodiments, the extended release coatingcomprises ethyl cellulose, at least one of povidone and hydroxypropylmethyl cellulose, and a plasticizer. In some embodiments, the pelletcore comprises amantadine, or a pharmaceutically acceptable saltthereof, and a binder coated onto a core seed. In some embodiments,based on the combined weight of the pellet core and extended releasecoating, the amantadine is present in amounts from 40 to 60 wt %, thebinder is present in amounts from 8 to 25 wt %, the core seed is presentin amounts from 1 to 25 wt %, the ethyl cellulose is present in amountsfrom 10 to 20 wt %, the povidone is present in amounts from 1 to 4 wt %,and the plasticizer is present in amounts from 1 to 4 wt %. In someembodiments, the composition further comprises a seal coating betweenthe pellet core and the extended release coating. In some embodiments,the pellet core comprises a binder selected from the group consisting ofhydroxypropyl methyl cellulose, copovidone, and mixtures thereof. Insome embodiments, the plasticizer is selected from the group consistingof medium chain triglycerides, diethyl phthalate, citrate esters,polyethylene glycol, glycerol, acetylated glycerides and castor oil.Some embodiments comprise treating Parkinson's disease in a humansubject in need thereof.

Some embodiments herein provide a pharmaceutical composition suitablefor once daily oral administration to a patient in need thereof saidcomposition comprising a therapeutically effective amount of amantadineor a pharmaceutically acceptable salt thereof in an extended releaseform which can be administered as not more than two size 0 or smallercapsules in a single daily administration. In some embodiments, thecomposition comprises 110-220 mg of amantadine or pharmaceuticallyacceptable salt thereof. In some embodiments, the composition has an invitro dissolution profile of amantadine of not more than 25% at 2 hours,40-80% at 6 hours, and at least 80% at 12 hours, using a USP ApparatusII (Paddles) at 50 rpm with 500 ml water at 37° C. as the dissolutionmedium. In some embodiments, the composition comprises a plurality ofpellets, each pellet comprising: (a) a pellet core comprisingamantadine, or a pharmaceutically acceptable salt thereof, and (b) anextended release coating surrounding the pellet core. In someembodiments, the extended release coating comprises ethyl cellulose, atleast one of povidone and hydroxypropyl methyl cellulose, and aplasticizer. In some embodiments, the pellet core comprises amantadine,or a pharmaceutically acceptable salt thereof, and a binder coated ontoa core seed. In some embodiments, the composition comprises amantadineand, based on the combined weight of the pellet core and extendedrelease coating, the amantadine is present in amounts from 40 to 70 wt%. In some embodiments, the pellet core comprises a core seed comprisingsugar or microcrystalline cellulose that is between 100 and 500 micronsin diameter. In some embodiments, the bulk density is between 0.5 and 1gm/cm³. In some embodiments, the composition comprises a seal coatingbetween the pellet core and the extended release coating. In someembodiments, the pellet core comprises a binder selected from the groupconsisting of hydroxypropyl methyl cellulose, copovidone, and mixturesthereof. In some embodiments, the plasticizer is selected from the groupconsisting of medium chain triglycerides, diethyl phthalate, citrateesters, polyethylene glycol, glycerol, acetylated glycerides and castoroil.

Some embodiments herein provide a method of treating Parkinson's diseasein a human subject, said method comprising orally administering acomposition comprising a therapeutically effective amount of amantadineor a pharmaceutically acceptable salt thereof in an extended releaseform which can be administered as not more than two size 0 or smallercapsules in a single daily administration. In some embodiments, thecomposition comprises 110-220 mg of amantadine or pharmaceuticallyacceptable salt thereof. In some embodiments, the composition has an invitro dissolution profile of amantadine of not more than 25% at 2 hours,40-80% at 6 hours, and at least 80% at 12 hours, using a USP ApparatusII (Paddles) at 50 rpm with 500 ml water at 37° C. as the dissolutionmedium. In some embodiments, the composition comprises a plurality ofpellets, each pellet comprising: (a) a pellet core comprisingamantadine, or a pharmaceutically acceptable salt thereof, and (b) anextended release coating surrounding the pellet core. In someembodiments, the extended release coating comprises ethyl cellulose, atleast one of povidone and hydroxypropyl methyl cellulose, and aplasticizer. In some embodiments, the pellet core comprises amantadine,or a pharmaceutically acceptable salt thereof, and a binder coated ontoa core seed. In some embodiments, the composition comprises amantadineand, based on the combined weight of the pellet core and extendedrelease coating, the amantadine is present in amounts from 40 to 70 wt%. In some embodiments, the pellet core comprises a core seed comprisingsugar or microcrystalline cellulose that is between 100 and 500 micronsin diameter. In some embodiments, the bulk density is between 0.5 and 1gm/cm³. In some embodiments, the composition comprises a seal coatingbetween the pellet core and the extended release coating. In someembodiments, the pellet core comprises a binder selected from the groupconsisting of hydroxypropyl methyl cellulose, copovidone, and mixturesthereof. In some embodiments, the plasticizer is selected from the groupconsisting of medium chain triglycerides, diethyl phthalate, citrateesters, polyethylene glycol, glycerol, acetylated glycerides and castoroil.

Some embodiments herein provide a method of treating levodopa induceddyskinesia in a human subject, said method comprising orallyadministering a composition comprising a therapeutically effectiveamount of amantadine or a pharmaceutically acceptable salt thereof in anextended release form which can be administered as not more than twosize 0 or smaller capsules in a single daily administration. Someembodiments herein provide a method of treating traumatic brain injuryin a human subject, said method comprising orally administering acomposition comprising a therapeutically effective amount of amantadineor a pharmaceutically acceptable salt thereof in an extended releaseform which can be administered as not more than two size 0 or smallercapsules in a single daily administration. Some embodiments provide amethod of treating traumatic brain injury in a human subject, saidmethod comprising orally administering a composition comprising atherapeutically effective amount of amantadine or a pharmaceuticallyacceptable salt thereof in an extended release form which can beadministered as not more than two size 0 or smaller capsules in a singledaily administration. Some embodiments provide a method of treatingfatigue in a human subject, said method comprising orally administeringa composition comprising a therapeutically effective amount ofamantadine or a pharmaceutically acceptable salt thereof in an extendedrelease form which can be administered as not more than two size 0 orsmaller capsules in a single daily administration. In some embodiments,the composition comprises 110-220 mg of amantadine or pharmaceuticallyacceptable salt thereof. In some embodiments, the composition has an invitro dissolution profile of amantadine of not more than 25% at 2 hours,40-80% at 6 hours, and at least 80% at 12 hours, using a USP ApparatusII (Paddles) at 50 rpm with 500 ml water at 37° C. as the dissolutionmedium. In some embodiments, the composition comprises a plurality ofpellets, each pellet comprising: (a) a pellet core comprisingamantadine, or a pharmaceutically acceptable salt thereof, and (b) anextended release coating surrounding the pellet core. In someembodiments, the extended release coating comprises ethyl cellulose, atleast one of povidone and hydroxypropyl methyl cellulose, and aplasticizer. In some embodiments, the pellet core comprises amantadine,or a pharmaceutically acceptable salt thereof, and a binder coated ontoa core seed. In some embodiments, the composition comprises amantadineand, based on the combined weight of the pellet core and extendedrelease coating, the amantadine is present in amounts from 40 to 70 wt%. In some embodiments, the pellet core comprises a core seed comprisingsugar or microcrystalline cellulose that is between 100 and 500 micronsin diameter. In some embodiments, the bulk density is between 0.5 and 1gm/cm³. In some embodiments, the composition comprises a seal coatingbetween the pellet core and the extended release coating. In someembodiments, the pellet core comprises a binder selected from the groupconsisting of hydroxypropyl methyl cellulose, copovidone, and mixturesthereof. In some embodiments, the plasticizer is selected from the groupconsisting of medium chain triglycerides, diethyl phthalate, citrateesters, polyethylene glycol, glycerol, acetylated glycerides and castoroil. In some embodiments, the method comprises administering thecomposition to a patient less than three hours before bed time.

The present invention may be better understood by reference to thefollowing examples, which are not intended to limit the scope of theclaims.

Example 1: Amantadine Extended Release Coated Pellet Formulations

Amantadine HCl extended release coated pellet compositions designed fornighttime administration were prepared using the components and relativeamounts shown in Table 1 below. For each composition, the drug coatingsolution was prepared by adding HPMC 5 cps and Copovidone to isopropylalcohol with continuous stirring. Purified water was added to thisdispersion and stirring continued until a clear solution is formed. Drug(Amantadine HCl) was then added to this binder solution and stirringcontinued until the drug was completely dissolved. Finally, talc wasadded and dispersed uniformly by stirring.

Celphere beads (screen sizes #35 to #50 i.e. 300 to 500 micron) wereloaded in a Wurster coating unit. The drug coating dispersion wassprayed onto the beads followed by a period of drying. The resultingdrug coated pellets were sieved to retain the fraction between screens#18 and #24 (approximately 700 μm to 1 mm diameter).

The seal coating solution was prepared by adding HPMC 5 cps to isopropylalcohol with continuous stirring. Purified water was added to thisdispersion and stirring continued until a clear solution was formed.Talc was added and dispersed uniformly by stirring. The sieved drugcoated pellets were loaded in a Wurster coating unit. The seal coatingdispersion was sprayed over the drug coated pellets followed by a periodof drying to remove the residual solvent and water in the pellets. Theresulting seal coated pellets were sieved to retain the fraction betweenscreens #18 and #24.

The ER coating solution was prepared by dissolving ethyl cellulose(viscosity 7 cps) in isopropyl alcohol and purified water and stirringuntil a clear solution was formed. Povidone K-90 was then dissolved inthis clear solution followed by addition of plasticizer Miglyol 812Nwith continuous stirring to form a clear solution. The sieved sealcoated pellets were loaded in a Wurster coating unit. The ER coatingsolution was sprayed over the seal coated pellets followed by a periodof drying to affect the ER coat and remove the residual solvent andwater in the pellets. After drying, magnesium stearate was spread on thetop bed of the coated pellets in the annulus region followed byrecirculation of the pellets in the Wurster unit to blend the magnesiumstearate with the coated pellets. The resulting ER coated pellets weresieved to retain the fraction between screens #18 and #24.

The desired weight of the ER coated pellets containing the unit dosewere filled into empty 1 hard gelatin capsule shell (size 1 for 100-140mg strength) using an encapsulator equipped with pellet dosing chamber.

TABLE 1 Composition of amantadine HCl ER capsules combined w/w ofComponent Function capsule Pellet Core Amantadine Hydrochloride USPActive 40-50% Microcrystalline cellulose spheres Core seeds 10-15%(Celphere ®) Hydroxypropyl methyl cellulose Binder 10-15% 5 cps USPCopovidone Binder 1-5% Talc USP Anti-tack 1-5% Isopropyl alcohol Solvent—¹ Water Solvent —¹ Seal Coating (optional) Hydroxypropyl methylcellulose Coating polymer  5-10% 3 cps USP Talc USP Anti-tack 0-5%Isopropyl alcohol Solvent —¹ Water Solvent —¹ Extended Release CoatingEthyl cellulose Coating polymer 10-20% Povidone Pore former 1-5% Mediumchain triglycerides Plasticizer 1-5% Isopropyl alcohol Solvent —¹ WaterSolvent —¹ Magnesium Stearate NF Lubricant 0-1% Density of pellets0.6-0.9 gm/cm³ NF = National Formulary ¹Purified water and isopropylalcohol are removed during processing.

The in vitro dissolution of capsules prepared above was tested using aUSP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37° C. as thedissolution medium. Capsules meeting desired dissolution specificationsreleased not more than 25% of the drug in 2 hours, 40-80% in 6 hours,and at least 80% at 12 hours. In an exemplary dissolution profile, therewas 0% drug release at 1 hour, 12% release at 2 hours, 43% release at 4hours, 68% release at 6 hours, 83% release at 8 hours, 92% release at 10hours, and 97% release at 12 hours. Capsules prepared in accordance withthe above method exhibited good shelf-stability, and batch-to-batchreproducibility upon scale-up.

Example 2: Amantadine Extended Release Coated Pellet Formulation withHigher Drug Loading

Amantadine HCl extended release coated pellet compositions designed fornighttime administration are prepared using the components and relativeamounts shown in Table 2 below and the manufacturing process describedin example 1.

The diameter of the inert cores is 200-300 microns. The diameter of thecoated pellets is 600-1200 microns. The bulk density of the coatedpellets is 0.7-1.2 g/cm³.

The desired weight of the ER coated pellets containing the unit dose arefilled into an empty hard gelatin capsule shell (size 1 for 170 mgstrength) using an encapsulator equipped with pellet dosing chamber.

TABLE 2 Composition of amantadine HCl ER capsules combined w/w ComponentFunction of capsule Pellet Core Amantadine Hydrochloride USP Active50-65% Microcrystalline cellulose spheres Core seeds  1-15% (Celphere ®)Hydroxypropyl methyl cellulose USP Binder  5-25% Copovidone Binder 1-5%Talc USP Anti-tack 1-5% Isopropyl alcohol Solvent —¹ Water Solvent —¹Seal Coating (optional) Hydroxypropyl methyl cellulose USP Coatingpolymer  0-10% Talc USP Anti-tack 0-5% Isopropyl alcohol Solvent —¹Water Solvent —¹ Extended Release Coating Ethyl cellulose Coatingpolymer 10-20% Povidone Pore former 1-5% Medium chain triglyceridesPlasticizer 1-5% Isopropyl alcohol Solvent —¹ Water Solvent —¹ MagnesiumStearate NF Lubricant 0-1% NF = National Formulary ¹Purified water andisopropyl alcohol are removed during processing.

The in vitro dissolution of capsules prepared above are tested using aUSP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37° C. as thedissolution medium and release not more than 25% of the drug in 2 hours,40-80% in 6 hours, and at least 80% at 12 hours.

Example 3: Amantadine Extended Release Coated Pellet Formulations

Amantadine HCl extended release coated pellet compositions suitable fornighttime administration were prepared using the components and relativeamounts shown in Table 3 below and the manufacturing process describedin Example 1.

The desired weight of the ER coated pellets containing the unit dose wasfilled into empty #1 hard gelatin capsule shell (100 mg strength) usingan encapsulator equipped with pellet dosing chamber.

TABLE 3 Composition of amantadine HCl ER capsules combined w/w ofcapsule Component Function A B C Pellet Core Amantadine Active 50.15% 47.94%  45.15%  Hydrochloride USP Microcrystalline Core 14.33%  13.70% 12.90%  cellulose spheres seeds (Celphere ®) Hydroxypropyl methyl Binder13.37%  12.79%  12.04%  cellulose USP Copovidone Binder 3.34%  3.2%3.01% Talc USP Anti-tack 2.51%  2.4% 2.26% Isopropyl alcohol Solvent —¹—¹ —¹ Water Solvent —¹ —¹ —¹ Seal Coating (optional) Hydroxypropylmethyl Coating 7.61% 7.27% 6.85% cellulose USP polymer Talc USPAnti-tack 0.76% 0.73% 0.69% Isopropyl alcohol Solvent —¹ —¹ —¹ WaterSolvent —¹ —¹ —¹ Extended Release Coating Ethyl cellulose Coating 6.23%9.46% 13.53%  polymer Povidone Pore 0.85% 1.29% 1.84% former Mediumchain Plasticizer 0.75% 1.13% 1.62% triglycerides Isopropyl alcoholSolvent —¹ —¹ —¹ Water Solvent —¹ —¹ —¹ Magnesium Stearate NF Lubricant 0.1%  0.1%  0.1% NF = National Formulary ¹Purified water and isopropylalcohol are removed during processing.

The in vitro dissolution of capsules prepared above were tested using aUSP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37° C. as thedissolution medium. The results are shown in FIG. 1.

Example 4: Amantadine Extended Release Formulation Made by ExtrusionSpheronization

Amantadine HCl extended release compositions designed for nighttimeadministration are prepared using the components and relative amountsshown in Table 4 below and the manufacturing process described below.

A blend of amantadine HCl, microcrystalline cellulose and lactosemonohydrate was prepared and a wet mass is prepared in a high sheargranulator using an aqueous solution of povidone. The wet mass isextruded using 1 mm sieve and extruded mass is spheronized using aspheronizer. The pellets are dried in a tray drier to yield corepellets. The core pellets are coated with extended release coatingsolution in a pan coater. The desired weight of the ER coated pelletscontaining the unit dose is filled into empty 1 hard gelatin capsuleshell (170 mg strength) using an encapsulator equipped with pelletdosing chamber.

TABLE 4 Composition of amantadine HCl ER capsules combined ComponentFunction w/w of capsule Pellet Core Amantadine Hydrochloride USP Active59.40% Microcrystalline cellulose Diluent 18.67% Lactose monohydrateDiluent 6.15% Povidone Binder 0.64% Water Solvent —¹ Extended ReleaseCoating Ethyl cellulose Coating polymer 12.41% Polyethylene glycol Poreformer 1.24% Dibutyl sebacate Plasticizer 1.49% Ethanol Solvent —¹

The in vitro dissolution of capsules prepared above are tested using aUSP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37° C. as thedissolution medium and release not more than 25% of the drug in 2 hours,40-80% in 6 hours, and at least 80% at 12 hours.

Example 5: Pharmacokinetic Measurement of Formulations of Amantadine ERCompared to IR Amantadine

Objective: The primary objective of the study was to confirm the PKproperties of extended release formulations in example 3, to determinethe pharmacokinetic profiles, safety and tolerability of three prototypeformulations of ER capsules of amantadine HCl described with differentrelease properties in Example 3 relative to a 100 mg film-coated IRamantadine HCl tablet (SYMMETREL®) given as single doses to healthyadult subjects under fasting conditions.

Study design: This was a Phase 1, randomized, single dose, open-label,four-period, crossover, fasting pharmacokinetic study in which single100 mg doses of three formulations of Amantadine ER capsules withdifferent release properties were compared to single 100 mg doses ofmarketed amantadine IR tablets (SYMMETREL®). The three ER formulationsdiffered in the amantadine release rates in vitro, as shown in FIG. 1.

Methods: Subjects were admitted to the unit for the first period ofdosing within 21 days of study screening. Subjects were dosed on the dayafter checking into the unit and discharged at 24 hours post dose.Subjects were asked to return after discharge for follow-up visits at 56hours and 152 hours after dosing. Each dosing period was separated by atleast 7 day washout.

After an overnight fast, the formulation was administered to thesubjects while in a sitting position with 240 mL of water. Blood sampleswere collected at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 18, 24 (discharge), and 56 hours following each dose.Plasma samples were assayed for amantadine by a validated liquidchromatography/tandem mass spectroscopy (LC/MS/MS) method.Pharmacokinetic parameters were calculated using a non-compartmentalanalysis with WinNonlin software (version 4.1 or higher; PharsightCorporation).

An analysis of variance (ANOVA) was performed on the natural logarithmsof Cmax and AUC0-∞ determined from the data following a single dose ofstudy drug using linear mixed effects model. The model included effectsfor subject, sequence, period, and regimen. The effects of sequence,period, and regimen were fixed, while the effect of subject was random.Ratio of ER to IR for both AUC (relative bioavailability for ERformualtions) and Cmax was calculated. (Adverse events were monitoredthroughout the study. Vital signs (pulse rate, blood pressure and bodytemperature), clinical laboratory measures (biochemistry, hematology,and urinalysis) and ECGs were collected at various times during thestudy.

Results: A total of 20 subjects participated in the study. The mean agewas 25.5 years old (range 20-38 years). The study consisted of 8 male(40%) and 12 female (60%) subjects with a mean body mass index (BMI) of23.6 kg/m2±2.85. The racial makeup was 100% Caucasian. Fifteen subjectsreceived all 4 treatments.

The PK results from this study showed that all three of the AmantadineER formulations reduced the rate of absorption, based on the reducedvalues of Cmax and increased Tmax, compared to SYMMETREL® (Table 5,FIGS. 5, 6). The IR formulation had the highest mean Cmax (277±73.9ng/mL) and shortest median Tmax (4 h) values. Formulations A, B, and Cproduced progressively lower Cmax and longer Tmax values. Cmax decreasedfrom 204±61.4 to 166±34.8 to 149±34.4 ng/mL, and median Tmax increasedfrom 7.0, to 11.0, to 14.0 h for formulations A, B, and C, respectively.Total amantadine exposure, as measured by AUC0-∞, was slightly lower inall three Amantadine ER formulations than SYMMETREL® but all threeformulations had acceptable bioavailability (85-95%).

TABLE 5 Single Dose Pharmacokinetic Parameters of Three Formulations ofAmantadine ER (Formulation A, B, and C), as Compared to SYMMETREL ®(Formulati_(on) IR) 100 mg 100 mg 100 mg 100 mg Formulation AFormulation B Formulation C F_(orm)ulation IR Parameter^(a) (n = 19⁾ (n= 17) (n = 18) (n = 18) C_(max) (ng/mL)  204 _(±) 61 166 ± 35  149 ± 34 277 ± 74  T_(max) (h) [range] 7 [5-11] 11 [5-15] 14 [₉₋₁8] 4 [2-6]A_(UC0-last) (ng * h_(/mL)) 5064 ± 1573 5028 ± 2328 4525 ± 1268 5488 ±1730 AUC_(0-∞) (ng * h/mL) 5545 ± ₁₉04 5724 ± 2369 5652 ± 2581 5907 ±1907 t_(1/2) (h)  13.9 ± 3.0 16.3 ± 5.2  18.3 ± 7.5  12.3 ± 3.5  ^(a)Allparameters are reported as the mean ± standard deviation (SD), exceptt_(max) which is reported as a median value (min to max range)

TABLE 6 Ratio ER/IR for C_(max) and AUC_(0-∞) Comparison VariableER/IR^(a) A vs. IR C_(max) (ng/mL) 66.0% AUC_(0-∞) (ng * h/mL) 85.3% Bvs. IR C_(max) (ng/mL) 60.9% AUC_(0-∞) (ng * h/mL) 94.6% C vs. IRC_(max) (ng/mL) 51.2% AUC_(0-∞) (ng * h/mL) 88.5% ^(a)Point estimate ofthe geometric mean ratio (ER/IR).

Example 6: Food-Effect Evaluation of Amantadine ER

Objective:

The primary objective was to demonstrate that the amantadine ERformulations suitable for nighttime administration exhibit excellentbioavailability when administered with food. We determined thepharmacokinetics of a 100 mg capsule of an amantadine ER formulation(Example 3, Formulation B), when administered both with a high fat mealand in a fasted state.

Study Design:

This was a Phase 1, randomized, single dose, open-label, two-period,crossover, food-effect study to compare single 100 mg doses ofFormulation I in healthy adult (18 to 45 years of age) male and femalesubjects in fed and fasted states. The study consisted of a 21-day to −2day screening phase (prior to the scheduled dosing day) and twotreatment periods, Period 1 and Period 2, with an 8-day wash-out periodbetween treatment periods.

Methods:

After an overnight fast, the formulation was administered to thesubjects while in a sitting position with 240 mL of water at ambienttemperature for the fasted condition. For the fed condition, after theovernight fast, subjects were served a high fat and high calorie testmeal (Guidance for Industry Food-Effect Bioavailability and FedBioequivalence Studies, December 2002) as breakfast, which they wererequired to consume completely within 30 minutes before taking the studymedication. Subjects were randomized to one of two sequences, eachcomposed of treatment administration under fed and fasted conditionsseparated by an eight day wash out period.

For each period, pharmacokinetic blood samples were collected atpre-dose and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,18, 24, 28, 48, 72, 96 and 144 hours after dosing in each period.Subjects were housed in the clinical facility at least 15 hours beforeinvestigational product administration and remained in the clinicalfacility for at least 28 hours after administration of theinvestigational product in each period. Samples after 28 hours in eachperiod were collected on an ambulatory basis. Amantadine in plasma wasquantified by a validated LC/MS/MS method. The pharmacokineticparameters were calculated from the drug concentration-time profile bynon-compartmental model using WinNonlin Professional Software-Version5.0.1 (Pharsight Corporation, USA) for amantadine. Absence of foodeffect was defined as met if the point estimates and 90% confidenceintervals (CI) for the ln-transformed C_(max), AUC_(last) and AUC_(∞)fed/fasting ratios of the population means were entirely within thestandard accepted range of 80% to 125%. All statistical analyses foramantadine were performed using PROC MIXED of SAS® Release 9.1.3 (SASInstitute Inc., USA).

Routine safety monitoring was conducted during and after dosing in allsubjects.

Results:

A total of 26 subjects participated in the study, 19 (73%) male and 7(27%) female. The mean age was 26 years (range 19-44) and the mean BMIwas 22.4 kg/m² (range 18.1-29.8). The racial makeup was 100% Asian. Allsubjects received at least one dose of study drug and were included inthe safety analysis. Twenty-four (92.3%) subjects completed the studyand were included in the pharmacokinetic analysis. Two subjects (7.7%)were withdrawn prior to completion of the study due protocol deviations.

The results of this study (Table 7) indicate that the single dosepharmacokinetics of Formulation B are not affected by food. The rate, asmeasured by C_(max), and the extent, as measured by AUC_(0-last) andAUC_(0-∞), of absorption of amantadine, administered with and withoutfood, were equivalent (Table 8).

TABLE 7 Mean ± SD Pharmacokinetic Parameters after Single DoseAdministration of 100 mg of Formulation B in Fed and Fasted States Mean± SD (Un-transformed data) n = 24 Parameters (Units)^(a) Fasted StateFed State T_(max) (h)  11.9 ± 2.1 (8-15)   9.5 ± 2.4 (5-16) C_(max)(ng/mL)  198.8 ± 34.7  219.4 ± 41.5 AUC_(0-last) (ng * h/mL) 5571.2 ±1654.2 5394.4 ± 1581.5 AUC_(0-∞) (ng * h/mL) 5663.1 ± 1677.4 5476.6 ±1590.7 t_(1/2) (h)  11.9 ± 2.8  11.5 ± 2.0 t_(lag) (h) 1.0 2.0 ^(a)Allparameters are reported as the mean ± standard deviation (SD). t_(max)is reported as the mean ± SD (min to max range).

TABLE 8 Geometric Least Squares Mean, Ratios and 90% Confidence Intervalfor Formulation B (n = 24) in Fed and Fasted States ln-transformed data90% Geometric Least Squares Mean Confidence Fed Fasted Ratio (Fed/Interval Parameters (Units) State State Fasted)% (Parametric) C_(max)(ng/mL) 215.6 195.8 110.1 104.4-116.2%  AUC_(0-last) (ng * h/mL) 5195.95344.2 97.2 91.0-103.8% AUC_(0-∞) (ng * h/mL) 5280.3 5434.7 97.290.9-103.8%

Conclusion:

The results of this study indicate that the single dose pharmacokineticsof amantadine ER are not affected by food. The rate, as measured byC_(max), and the extent, as measured by AUC_(0-last) and AUC_(0-∞), ofabsorption of amantadine, administered with and without food, wereequivalent.

Example 7: Pharmacokinetic Study Comparing Once-Daily Administration ofAmantadine HCl ER Capsules with Twice-Daily Administration of AmantadineHCl IR Tablets in Healthy Adults Under Fasting Conditions

Objective: The primary objective of this study was to measure at steadystate under repeat or chronic dosing the pharmacokinetics of an ERamantadine formulation suitable for nighttime administration, and enablethe calculation of critical PK parameters for future safety and efficacystudies (i.e., Cave-morning, Cave-day, Cave-night) of ER amantadineformulations administered at night. We compared the single dose andrepeat dose pharmacokinetics of amantadine HCl administered twice dailyas a commercially available immediate release (IR) formulation to a oncedaily amantadine extended release (ER) formulation (Example 3,Formulation B).

Study Design:

This was a two period, multiple dose, crossover study. After a 21 dayscreening period, 26 healthy male and female subjects were randomized toreceive one of two treatments (amantadine ER 200 mg once daily oramantadine IR 100 mg twice daily) in Period-I, then crossed over toreceive the other treatment in Period-II.

Methods:

Study drug administration started on day 1. Study drug was notadministered on Day 2. Multiple dosing commenced on day 3 and continuedfor 7 days (through day 9). A washout period of 8 days separated thedose administrations. The study drug was administered with 240 mL ofdrinking water. No other fluids were allowed within 1 hour of dosing.For each period, pharmacokinetic blood samples were collected atpre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18,20, 24, 28, 36, and 48 hours after the first dose. The morning trough(pre-dose) blood samples were collected on Days 7 and 8. Blood sampleswere again collected immediately before the morning dose on Day 9 and at1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 24, 28, 48,72, and 96 hours thereafter. Samples after 28 hours following themorning dose on day 9 were collected on an ambulatory basis in eachperiod. Amantadine in plasma was quantified by a validated LC/MS/MSmethod. The pharmacokinetic parameters were calculated from the drugconcentration-time profile by non-compartmental model using WinNonlinProfessional Software-Version 5.0.1 (Pharsight Corporation, USA) foramantadine.

Statistical analyses were conducted to assess the pharmacokineticprofile of single dose and repeat dose amantadine HCl administered twicedaily as a commercially available immediate release (IR) formulationcompared to a once daily extended release (ER) formulation (FormulationB). An analysis of variance (ANOVA) was performed on the naturallogarithms of C_(max), C_(min), and AUC₂₄ determined from the datafollowing the dose of study drug on study day 9 using linear mixedeffects model. The model included the fixed effects for sequence,period, regimen and a random subject effect. The confidence intervalswere used to perform the 2 one-sided tests procedure for equivalenceassessment. The confidence intervals were obtained by exponentiating theendpoints of the confidence intervals for the difference of meanlogarithms obtained within the framework of the ANOVA model. The upperand lower limits of confidence intervals from the natural-logtransformed data were back-exponentiated to obtain the 90% confidenceinterval for the ratio of geometric means. Equivalence was establishedif the exponentiated 90% confidence interval fell entirely within theinterval (80.00%, 125.00%).

Repeated measures ANOVA was carried out for comparison of C_(min) forday 7, 8 and 9 at 5% level of significance on both untransformed andln-transformed data. Steady state was demonstrated if the repeatedmeasures ANOVA test was found to be non-significant. The statisticalanalysis for amantadine was performed using PROC MIXED of SAS® Release9.1.3 (SAS Institute Inc., USA).

Routine safety monitoring was conducted during and after dosing in allsubjects, and at the end of the study.

Results:

A total of 26 subjects participated in the study, 22 (84.6%) male and 4(15.4%) female. The mean age was 26 years (range 19-42) and the mean BMIwas 22.9 kg/m² (range 18.1-28.8). The racial makeup was 100% Asian. Allsubjects received at least one dose of study drug and were included inthe safety analysis. Twenty-four (92.3%) subjects completed the studyand were included in the pharmacokinetic analysis. Two subjects (7.7%)were withdrawn from the PK analysis prior to completion of the study dueto vomiting within 12 hours of dosing, which was a pharmacokineticexclusion criterion.

As expected from its half-life, once daily administration of amantadineER and twice daily dosing of amantadine IR resulted in accumulation asmeasured by higher C_(max) and AUC on Day 9 compared to Day 1 (Table 9and FIG. 2). Steady state was achieved by Day 9 for both formulations asdemonstrated by similar trough levels on Days 7, 8 and 9 (data notshown). At steady state (Day 9) plasma concentrations (FIG. 2, Table 9)and pharmacokinetic parameters (Table 9) were comparable for bothformulations. Furthermore, the formulations are equivalent in terms ofthe extent and the rate of absorption of amantadine as measured bysteady state C_(max), C_(min) and AUC₀₋₂₄ (Table 9), where equivalencyis defined by the 90% CIs of the ratio of the least square means of thetest versus reference for steady state C_(max), C_(min) and AUC₀₋₂₄ ofAmantadine ER to Amantadine IR falling within 80%-125%.

TABLE 9 Mean (±SD) Pharmacokinetic Parameters of Amantadine after Singleand Multiple Dose Administration of IR (100 mg BID) and ER (200 mg QD)Formulations Formulation IR ER (n = 24) (n = 24) Parameter (Units)^(a)Day 1 Day 9 Day 1 Day 9 t_(1/2) (h) 13.2 ± 2.8 12.6 ± 2.4 13.7 ± 3.612.8 ± 2.2   [9.1-18.8]  [9.4-18.1]  [9.1-22.7]  [9.2-17.4] t_(max) (h)14.42 ± 0.88 12.6 ± 4.5 11.4 ± 1.9 10.3 ± 2.0   [13-16]  [1-15]  [8-18] [8-18] C_(max) (ng/mL) 530 ± 80  728 ± 153 431 ± 84 665 ± 179 [407.5-752.7]  [538.4-1101.8]  [313.5-559.9]  [444.4-1140.0]AUC_(0-last) (ng h/mL) 11989 ± 2224 23040 ± 8273 11171 ± 2773 21362 ±8946   [9243-17106]  [13133-46446]  [7326-16970] [10821-47134] AUC_(0-∞)(ng h/mL) 13685 ± 3324 NA 12900 ± 4087 NA  [10167-20989]  [7817-22153]AUC₀₋₂₄ (ng h/mL)  7695 ± 1026 13752 ± 3586  7173 ± 1367 12680 ± 3879  [5967-10171]  [9085-22519]  [5021-9552]  [7896-23058] C_(min) (ng/mL) — 412.4 ± 142.6 — 374.9 ± 151.7  [218.5-795.2] [172.2-767.1] ^(a)Allparameters are reported as the mean ± SD, [min to max range] NA = notapplicable

Certain additional PK parameters that are important in determining thesuitability of the ER amantadine formulation for once daily, night timeadministration are also reported in Table 10.

TABLE 10 Additional Steady State PK parameters of Amantadine ER ER IR200 mg QD 100 mg BID Cmax/Cmin 1.86 1.68 C-ave-8-16 hrs (ng/ml) 614 586C-ave-8-12 hrs (ng/ml) 643 510 C-ave-16-24 hrs (ng/ml) 502 569 C-ave-0-8hrs (ng/ml) 465 586 C-ave-8-16 hrs/C-ave-0-8 hrs 1.32 1.00 C-ave-8-12hrs/C-ave-0-8 hrs 1.38 0.87 % Change in Plasma Concentration 0-3 hrs  5%55% % Change in Plasma Concentration 0-4 hrs 23% 48% AUC 0-4 as % of AUC24 12% N/A AUC 0-8 as % of AUC 24 30% N/A AUC 0-12 as % of AUC 24 51%N/A

Conclusion: the ER amantadine formulation exhibits the desired steadystate PK properties that would make the same suitable for administrationat night and for achieving desired efficacy and tolerability benefits.Specifically, the ER amantadine formulation administered once daily atnight results in relatively slow initial rise in amantadine plasmaconcentration, higher average amantadine plasma concentrations 8 to 12hours after administration relative to 0-8 hours after administrationand thus if administered at night higher ratios of average day time tonight time amantadine plasma concentrations relative to IR amantadine.Thus this formulation is well suited for administration at higher dosesthan current practice that are expected to be relatively well toleratedand potentially provide superior efficacy in the treatment of LID,fatigue and Parkinson's disease.

Example 8: Study Comparing Administration of Amantadine HCl ER CapsulesOnce Nightly with Twice-Daily Administration of Amantadine HCl IRTablets in Normal Healthy Volunteers

Objective: The primary objective is to compare the effects on sleep ofamantadine extended release (ER) capsules (Formulation B) administeredonce daily at bedtime with amantadine immediate release (IR) tabletsadministered twice daily in normal healthy volunteers. This ERformulation exhibits a Cave,day/Cave, night=1.30.

Study Design:

This is a single-center, double-blind, triple-dummy, randomized,crossover study to compare the effects on sleep of amantadine ERcapsules, QHS, amantadine IR tablets BID, and caffeine caplets (activecomparator) in 30 normal healthy volunteers as assessed by overnightpolysomnography (PSG) and standardized questionnaires (StanfordSleepiness Scale (SSS); Modified Epworth Sleepiness Scale(m-ESS)/Karolinska Sleepiness Scale (KSS); Toronto Hospital AlertnessTest (THAT)/ZOGIM Alertness Scale (ZOGIM-A); Visual analog scale ofsleepiness/alertness (VAS)).

Study drugs are administered in 3 dosing periods. A single day's dosageof one drug is administered per dosing period. Each day of dosing isseparated by a washout period of 1 week. A single day's dosage ofamantadine ER (Formulation B) consists of one 220 mg capsule (or 2×110mg capsule) administered at bed time (QHS; defined as 23:00 h for thepurposes of this study). A single day's dosage of amantadine IR consistsof one 100 mg capsule administered twice a day (BID; defined as 8:00 hand 16:00 h for the purposes of this study). A single day's dosage ofcaffeine consists of one 100 mg capsule administered three times a day(TID; defined as 8:00 h, 16:00 h, & 23:00 h for the purposes of thisstudy).

All subjects are dosed three times a day, at 8:00 h, 16:00 h, & 23:00 h.At each hour of dosing, every subject receives either the active drug orthe matching placebo for each of the 3 treatments. Whether the capsule,tablet, or caplet administered at a specific hour of dosing containsactive study drug or is a placebo dummy is determined according to thedosing sequence and period to which the subject is assigned.

Consented subjects who meet eligibility criteria are randomized equallyto one of 3 treatment sequences (groups), each comprising 3 single-daytreatment periods separated by 1 week washout periods as describedabove. Additionally, there is a one-day, single-blind, placebo run-inprior to each double-blind dosing day. This is to allow subjects toacclimate to sleeping in the Clinical Research Unit (CRU) underconditions of PSG recording and to establish individual baseline (BL)PSG characteristics.

For each dosing period, subjects are admitted to a CRU equipped with asleep laboratory the day before the first day of dosing with activestudy drug. They stay in the CRU overnight and through the entirety ofthe active drug-dosing day. They again stay overnight and then aredischarged from the CRU the morning of the following day. For the firstdosing period, the day of admission to the CRU (Day −1) constitutes thelast day of the screening phase, and the day of discharge from the CRUconstitutes the first day of the first washout period (Day 2). For thesecond dosing period, the day of re-admission to the CRU (Day 7)constitutes the last day of the first washout period, and the day ofdischarge (Day 9) will constitute the first day of the second washoutperiod. For the third dosing period, the day of re-admission to the CRU(Day 14) constitutes the last day of the second washout period, and theday of discharge (Day 16) constitutes the first day of the follow-upphase.

On the day of admission (or re-admission) to the CRU, subjects undergoroutine laboratory and vital sign testing. They are administered oneeach of the placebo dummies (for amantadine ER, amantadine IR, &caffeine) at 16:00 h and at 23:00 h in single-blind fashion. They arequestioned for adverse events (AEs) and have vital signs checkedimmediately prior to each dosing. Blood is drawn for routine laboratorytesting and toxicology screen prior to the 16:00 h dosing. Subjectsspend the night in the sleep lab under conditions of PSG recording.

On the day of dosing with active study drug, subjects are awakened at7:00 h and fill out a battery of sleep and alertness questionnaires Theyreceive study drug (active or placebo) at 8:00 h, 16:00, and 23:00 h.They are questioned for AEs and have vital signs checked immediatelyprior to each dosing. Blood is drawn to measure plasma amantadineconcentrations prior to the 23:00 h dosing.

On the day after dosing with active study drug, subjects are awakened at7:00 h and fill out a battery of sleep and alertness questionnairesShortly before 8:00 h, i.e., 9 hours after the last dosing time, theyare questioned for AEs and have vital signs checked. Also, blood isdrawn to measure plasma amantadine concentrations. Instructions forcontacting the site to report any AEs are reviewed with the subjectsprior to their discharge from the CRU. The schedule for returning to thePSU for the next dosing period (this applies to returning for Periods 2& 3) or for telephone contact (this applies to the follow-up after thethird dosing period) is be reviewed.

All subjects receive a follow-up telephone call 3 days followingdischarge from the CRU (Day 19).

AEs and concomitant medications are monitored throughout the study.Blood samples for measurement of blood plasma concentrations are drawnimmediately prior to the 23:00 h dosing time on Days 1, 8, and 15, andat approximately 8:00 h on Days 2, 9, and 16.

Sleep parameters and measurements of sleepiness and alertness at eachtime point are listed by subject. Both composite scores and scores fromthe individual components of the PSG and questionnaires are tabulatedand analyzed. For each parameter measured, descriptive summarystatistics are calculated by sequence and treatment, including means (ormedians, as appropriate), ranges, and standard deviations (SDs).

Inferential statistics are performed on selected results wherein themagnitude of the differences between the means across treatment groupsrelative to the variance suggests a possible differential treatmenteffect. Continuous variable data is analyzed by parametric statistics(repeated measures analysis of variance with appropriate supplementalpost-hoc analyses and/or paired t-test). Categorical data and data notconforming to a normal distribution is analyzed by non-parametricstatistics (Wilcoxon signed rank test). PSG data may also be assessed bymultivariate analyses and/or spectral analyses.

Results:

A lack of increase in, or reduction of, sleep disturbances with QDadministration of 220 mg of amantadine ER compared to BID administrationof amantadine IR, as measured by PSG and a standardized sleepquestionnaire (e.g. SSS, m-ESS, KSS, THAT, ZOGIM-A, or VAS),demonstrates the suitability of amantadine ER for once dailyadministration at bedtime.

Example 9: Study Comparing the Effects on Sleep and Efficacy ofAmantadine HCl ER Capsules Administered Once Daily at Night Relative toAmantadine HCl IR Capsules Administered Twice Daily in Parkinson'sPatients

Objective:

To compare the effects on sleep and efficacy of amantadine extendedrelease (ER) capsules.

Study Design:

This is a Multi-Center, Double-Blind, Randomized Study to Compare theEffects on Sleep and Efficacy of Amantadine Extended Release (ER)Capsules in 120 Parkinsons Patients as assessed by UPDRS (UnifiedParkinson's Disease Rating Scale), UPDRS-IV (Unified Parkinson's DiseaseRating Scale Part IV), AIMS (Abnormal Involuntary Movement Scale),overnight polysomnography (PSG) and standardized questionnaires(Stanford Sleepiness Scale (SSS); Modified Epworth Sleepiness Scale(m-ESS)/Karolinska Sleepiness Scale (KSS); Toronto Hospital AlertnessTest (THAT)/ZOGIM Alertness Scale (ZOGIM-A); Visual analog scale ofsleepiness/alertness (VAS)).

All study drugs are administered orally. Treatment A consists of aplacebo capsule administered in the morning and two 110 mg capsules ofAmantadine (ER) and a placebo capsule administered at bed time.Treatment B consists of a placebo capsule administered in the morningand three 110 mg capsules of Amantadine (ER) administered at bed time.Treatment C consists of a 100 mg capsule of Amantadine IR administeredin the morning and a 100 mg capsule of Amantadine IR and two placebocapsules administered at bed time. Treatment D consists of a placebocapsule administered in the morning and 3 placebo capsules administeredat bed time.

Consented subjects who meet eligibility criteria are randomized equallyto one of 3 treatment groups, each comprising 14-day treatment periods.Additionally, there is a one-day, single-blind, placebo run-in prior toeach double-blind dosing day. This is to allow subjects to acclimate tosleeping in the Clinical Research Unit (CRU) under conditions of PSGrecording and to establish individual baseline (BL) PSG characteristics.

For each dosing period, subjects are admitted to a CRU equipped with asleep laboratory the day before the first day of dosing with activestudy drug. They stay in the CRU overnight and through the entirety ofthe active drug-dosing day. They again stay overnight and then aredischarged from the CRU the morning of the following day.

Parkinson's scores are recorded in the mornings on days 1, 7 and 14using standard scoring methods, including the UPDRS and AIM.

AEs and concomitant medications are monitored throughout the study.

Sleep parameters and measurements of sleepiness and alertness at eachtime point are listed by subject. Both composite scores and scores fromthe individual components of the PSG and questionnaires are tabulatedand analyzed. For each parameter measured, descriptive summarystatistics are calculated by sequence and treatment, including means (ormedians, as appropriate), ranges, and standard deviations (SDs).

Inferential statistics are performed on selected results wherein themagnitude of the differences between the means across treatment groupsrelative to the variance suggests a possible differential treatmenteffect. Continuous variable data is analyzed by parametric statistics(repeated measures analysis of variance with appropriate supplementalpost-hoc analyses and/or paired t-test). Categorical data and data notconforming to a normal distribution is analyzed by non-parametricstatistics (Wilcoxon signed rank test). PSG data may also be assessed bymultivariate analyses and/or spectral analyses.

Results:

An improvement in UPDRS, UPDRS-IV, AIM, lack of increase in, orreduction of, sleep disturbances, as measured by PSG and a standardizedsleep questionnaire (e.g. SSS, m-ESS, KSS, THAT, ZOGIM-A, or VAS),demonstrates the suitability of amantadine ER for once dailyadministration at bedtime.

Example 10. Simulated Pharmacokinetic Characteristics of HigherStrength, Amantadine ER Formulations Administered at Nighttime

Objective: The objective is to use the data generated in the clinicalstudy described in Example 7 to predict steady state plasmaconcentration-time profiles of various IR and ER amantadine regimens atdifferent dose levels to show the benefits of higher strength amantadineER formulations administered at nighttime.

Methodology: Plasma concentration-time profiles from healthy volunteersthat received multiple doses of the ER and IR formulations of amantadineper study procedures described in Example 7 (ADS-5101-MD-104) were usedto develop a pharmacokinetic model describing each of the twoformulations. This study was an open-label, randomized, two-treatment,two-period, two-way crossover study comparing once-daily amantadine ERcapsules and twice-daily amantadine IR tablets in 26 healthy, adult maleand female volunteers. Complete data from 24 individuals were used inthis exercise. Blood samples for pharmacokinetic evaluation werecollected after single dosing on Day 1 and at steady state on Day 9. Inthe first step of the analysis, WinNonlin 5.2.1 (Pharsight Corp.,Mountain View, Calif.) was used to fit a one-compartment model withfirst-order input and first-order output, weighted 1/y (where y is theamantadine plasma concentration), to each individual's plasmaconcentration-time data obtained after single (Day 1) and repeated (Day9) dose administration of amantadine IR and ER; the fitting was doneseparately for both formulations, but simultaneously for both days.Modeling assumptions employed include dose proportionality and constantclearance as a function of time.

The model is described by the following equation:

$\begin{matrix}{C = {\frac{FD}{V( {k_{a} - k} )}\lbrack {{\exp ( {- {k( {t - t_{{lag})}} )}} )} - {\exp ( {- {k_{a}( {t - t_{{lag})}} )}} )}} \rbrack}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

where C is the plasma concentration, F is the absolute bioavailability,D is dose, V is the volume of distribution, k_(a) is the absorption rateconstant, k is the elimination rate constant, t is time, and t_(lag) isthe lag time of absorption. The goodness of fit was verified bycomparing the individual model predicted and observed concentration-timedata from Study ADS-5101-MD-104. After Equation 1 was fitted to eachindividual's plasma concentration-time data, model parameter estimatesof V/F, k_(a), k, and t_(lag) were obtained for each of the 24 subjects.The goodness of the prediction at steady state was confirmed bycomparing the observed data and predicted steady-state concentrations ofamantadine obtained after daily dosing of 200 mg as the ER and IRformulations (Day 9).

In the second step of the analysis, individual model parameter estimateswere used to simulate steady-state concentration-time profiles for eachindividual for both formulations by reinserting the individual parameterestimates into Equation 1, and summing the contribution of 7 sequentialdays of dosing, according to the following dosing regimens:

-   -   1. Once Daily (QD) dosing of 260, 340, and 420 mg of the ER        formulation to steady state    -   2. Three times daily (TID) dosing of 100 mg of the IR        formulation to steady state    -   3. Twice daily (BID) dosing of 100 mg of the IR formulation to        steady state

Results: FIG. 4 shows the simulated steady state plasma concentrationtime profiles for various ER amantadine doses along with various regimesof IR amantadine. Table 11 summarizes values of the pharmacokineticparameters that affect the efficacy and tolerability of ER amantadinewhen administered at night.

TABLE 11 PK parameters associated with nighttime administration -morning peak benefit measured for ER Amantadine formulation IR 100 mg IR100 mg ER 260 mg ER 340 mg ER 420 mg BID TID QD QD QD Cmax (ng/ml) 669936 834 1091 1348 Cmin (ng/ml) 435 731 461 603 745 Cmax/Cmin 1.54 1.281.81 1.81 1.81 C-ave-day (6 am-4 pm) (ng/ml) 571 845 766 1002 1238C-ave-morn (6 am-10 am) (ng/ml) 479 870 824 1078 1332 C-ave-even (4pm-10 pm) (ng/ml) 522 852 591 773 955 C-ave-night (10 pm-6 am) (ng/ml)596 843 616 805 995 C-ave-day/C-ave-night 0.96 1.00 1.24 1.24 1.24C-ave-morn/C-ave-night 0.80 1.03 1.34 1.34 1.34 C-ave-day relative to100 mg BID 1.00 1.48 1.34 1.76 2.17 IR

As shown in Table 11 and in the figures, the ER amantadine formulationsadministered once daily at night result in higher ratios of average daytime to night time amantadine plasma concentrations relative to IRamantadine and are predicted to be relatively well tolerated. The ERformulations also result in average day time amantadine plasmaconcentrations that are 1.3 to 2.2 fold that of IR amantadineadministered at 100 mg twice daily and is predicted to result insignificantly enhanced efficacy when administered to patients in theclinical study described in Example 11 below.

Example 11: A Randomized, Double-Blind, Placebo-Controlled Study of theEfficacy and Safety of Amantadine Extended Release Oral Capsules for theTreatment of Levodopa-Induced Dyskinesia in Parkinson's Disease

Study Objectives: This study is designed to confirm dose range ofAmantadine Extended Release (ER) oral capsules dosed once daily atnighttime for the treatment of levodopa-induced dyskinesia (LID) insubjects with Parkinson's Disease (PD). In addition, the study isdesigned to demonstrate the safety and tolerability of Amantadine ERoral capsules dosed once daily for the treatment of LID in subjects withPD. Finally, to confirm the steady-state pharmacokinetics of theAmantadine ER dosing regimens in Parkinsons patients and to correlateC-ave-day,Cave-morning, C-ave-morning/C-ave-night andC-ave-day/C-ave-night with the efficacy and tolerability of amantadine.

Study Design:

This will be a multi-center, randomized, double-blind,placebo-controlled, 4-arm parallel group study of Amantadine ER insubjects with PD and LID/Consenting subjects who meet eligibilitycriteria will be randomized 1:1:1:1 to receive one of the following 4treatments, each administered as once daily, dosed at night, for 8weeks:

-   -   Treatment A: Placebo,    -   Treatment B: 260 mg Amantadine ER (ADS-5102),    -   Treatment C: 340 mg Amantadine ER (ADS-5102)    -   Treatment D: 420 mg Amantadine ER (ADS-5102)

Subjects who are randomized to Treatment C or D (higher dose amantadinegroups) will receive, in double-blind fashion, 260 mg Amantadine ER oncedaily during week 1, with an increase to either 340 mg or 420 mg oncedaily at the beginning of week 2. Dosing will continue through week 8.

Following completion of the baseline visit and randomization, subjectswill return to the clinic after 1, 2, 4, 6, and 8 weeks of dosing, witha follow-up visit 14 days following the last dose of study drug. Studyvisits and assessments will be scheduled during morning hours whenpossible (9 am through 1 pm). A set of two 24-hour diaries will becompleted during 48 hours prior to randomization and 48 hours prior toselected study visits. The diary will be used to score five differentconditions in 30-minute intervals: Sleep, OFF, ON without dyskinesias,ON with nontroublesome dyskinesias, ON with troublesome dyskinesias.

Blood samples will be collected at selected study visits fordetermination of amantadine plasma concentrations, and evaluation ofsteady-state population pharmacokinetics. Subject participation duringthe study will be up to 12 weeks and will include a 2-week (maximum)screening period, 8-week (maximum) treatment period, and a 2-weekfollow-up period. Subjects who are unable to tolerate their assignedstudy drug assignment will permanently discontinue study drug andcontinue to be followed for safety through 2 weeks following the lastdose of study drug.

Patient Eligibility Criteria:

Subjects are eligible to take part in the study if they meet theinclusion and do not meet the exclusion criteria. Selected key criteriaare as follows:

Inclusion Criteria:

-   -   Male or female adults, residing in the community (i.e. not        residing in an institution)    -   Between 30 and 75 years of age, inclusive    -   Ambulatory or ambulatory-aided (e.g. walker or cane) ability,        such that the subject can come to required study visits    -   Knowledgeable and reliable caregiver/study partner, if        appropriate, to accompany the subject to study visits    -   Signed a current IRB/IEC-approved informed consent form    -   Following training, the subject is willing and able to        understand and complete the 24-hour home diary (caregiver        assistance allowed)    -   Idiopathic Parkinson's Disease, complicated by dyskinesia (a        MDS-UPDRS score will be determined during screening, but a        minimum score is not required)    -   On a stable regimen of antiparkinson's medications, including        levodopa, for at least 30 days prior to screening, and willing        to continue that regimen during study participation    -   Presence of dyskinesia, defined as a minimum UDysRS score

Exclusion Criteria:

-   -   Presence of other neurological disease that may affect        cognition, including, but not limited to Alzheimer's dementia,        Huntington's disease, Lewy body dementia, frontotemporal        dementia, corticobasal degeneration, or motor or sensory        dysfunction secondary to stroke or brain trauma.    -   Presence of cognitive impairment, as evidenced by a Mini-mental        State Examination (MMSE) score of less than 24 during screening.    -   Presence of an acute major psychiatric disorder (e.g., Major        Depressive Disorder) according to DSM-IV-TR or symptom (e.g.,        hallucinations, agitation, paranoia) that could affect the        subject's ability to complete study assessments    -   Presence of sensory impairments (e.g., hearing, vision) that        would impair the subject's ability to complete study assessments    -   History of alcohol or drug dependence or abuse, according to        DSM-IV criteria, within 2 years prior to screening    -   History of seizures (excluding febrile seizures of childhood)    -   History of stroke or TIA within 2 years prior to screening    -   History of myocardial infarction, NYHA Congestive Heart Failure        Class 3 or 4, or atrial fibrillation within 2 years prior to        screening    -   History of cancer within 5 years prior to screening, with the        following exceptions: adequately treated non-melanomatous skin        cancers, localized bladder cancer, non-metastatic prostate        cancer or in situ cervical cancer (these exceptions must be        discussed with and approved by the Medical Monitor before study        entry)    -   Any of the following lab abnormalities; Hemoglobin <10 g/dL, WBC        <3.0×10⁹/L, Neutrophils <1.5×10⁹/L, Lymphocytes <0.5×10⁹/L,        Platelets <100×10⁹/L, Hemoglobin AlC >9%, or Aspartate        aminotransferase (AST) and/or alanine aminotransferase (ALT) >2        times the upper limit of normal    -   Estimated GFR <50 mL/min/1.73 m² by Modification of Diet in        Renal Disease (MDRD) or Cockcroft-Gault equation    -   Any clinically significant ECG abnormalities    -   Inability to swallow oral capsules, or a history of        gastrointestinal malabsorption that would preclude the use of        oral medication

Study Endpoints:

The primary efficacy endpoint will be the change from baseline to week 8in the Unified Dyskinesia Rating Scale (UDysRS) score. Key secondaryendpoints will include:

-   -   ON time without troublesome dyskinesia (ON without dyskinesia        plus ON with nontroublesome dyskinesia), based on a standardized        PD home diary    -   Unified Parkinson's Disease Rating Scale (MDS-UPDRS), overall        score    -   Fatigue as measured by the Fatigue Severity Scale (FSS). This        scale includes 9 questions that are completed by the patient        using a rating scale from 1 (strongly disagree) to 7 (strongly        agree). This fatigue scale is recommended by MDS for both        screening and severity rating (2010)    -   Safety, including adverse events, safety-related study drug        discontinuations, vital signs, and laboratory tests.

The following mixture of traditional and new scales have been selectedfor this phase 2 study:

-   -   Unified Dyskinesia Rating Scale (UDysRS) will be used for        primary outcome measure. This scale has four parts, and a total        possible score of 104:        -   I: Historical Disability (patient perceptions) of            On-Dyskinesia impact        -   II: Historical Disability (patient perceptions) of            Off-Dystonia impact        -   III: Objective Impairment (dyskinesia severity, anatomic            distribution, and type, based on 4 observed activities)        -   IV: Objective Disability based on Part III activities    -   ON time without troublesome dyskinesia, based on a standardized        Parkinson's Disease home diary (suggest Test Diary II), [33]        will be a secondary outcome measure. This scale has been used in        number of studies with mixed success [34]. However, most KOLs        feel that subject-reported dairy data must be collected, and        needs to support the primary outcome measure.    -   Unified Parkinson's Disease Rating Scale (UPDRS), part IV, items        32 (duration of dyskinesias: 0=none, 4=76-100% of the waking        day) and 33 (disability of dyskinesias: 0=not disabling,        4=completely disabling) will be a secondary outcome measure.        This scale is a traditional scale used in PD for many years and        these items have been utilized in most LID studies.    -   Cognitive Scales: Global caregiver impression, depression and        other scales will be employed to measure the mental status        benefits of ER amantadine.

Statistical Methods

Efficacy Analyses: The efficacy analysis population will include allrandomized and dosed subjects who provide at least one post-baselineefficacy assessment. For the efficacy endpoint of UDysRS score, thechange from baseline to week 8 will be analyzed using an analysis ofcovariance (ANCOVA) model with treatment group as a factor and theUDysRS baseline value as a covariate. The primary analysis will comparethe 260 mg ADS-5102 group to the placebo group using a two-sided test atthe 5% level of significance. If the primary comparison is statisticallysignificant (p<0.05), then the 340 mg and 420 mg ADS-5102 groups will becompared to placebo, also using a two-sided test at the 5% level ofsignificance.

The secondary endpoints will be analyzed using the same types of ANCOVAmodels as described for the primary endpoint. All secondary comparisonsbetween treatment groups will be performed using two-sided tests at the5% level of significance. A last observation carried forward (LOCF)approach will be utilized for missing data. The primary efficacyanalysis will be repeated for the per-protocol population, a subset ofthe efficacy analysis population who provide week 8 efficacyassessments.

Safety Analyses:

The safety analysis population will include all randomized subjects whoreceive at least one dose of study drug. All safety endpoints will beanalyzed from the time of first dose through the completion of follow-up(or 2 weeks following the last dose of study drug). A safety analysiswill also be done on the safety reported during the first 2 weeks ofstudy drug treatment, in order to assess tolerability of initial dosingwith ADS-5102 amantadine ER.

Results: following improvements are expected from this study are shownin the table below. Additional endpoints are described that

-   -   Significant (20-60%) reduction in dyskinesia score measured by        acceptable primary endpoint (e.g., UDysRS)    -   Increase in ON time without troubling dyskinesia by 20-60%    -   Improvement in UPDRS from 5% to 20%.    -   Improvement in Parkinson's fatigue (FSS) from 5% to 60%.    -   Improvement in mood by PGI from 5% to 20%.

% Clinical Instruments Effect (Placebo- for Dyskinesia Active/Placebo)Range of Scores Unified Dyskinesia 5-60% 0-104 (4 parts, 26 items RatingScale total, each 0, normal-4, (UDysRS) severe) Unified Parkinson's5-20% Disease Rating Scale (UPDRS, MDS revision) Part IV 5-60% 0-24 (6items, each 0, normal-4, severe) Part IV, dyskinesia items 5-60% 0-8 (2dyskinesia items, 4.1 only and 4.2, each 0, normal-4, severe)Parkinson's Disease 5-40% 0-100% (on time without Home Diary dyskinesiaor with (Hauser et al) nontroublesome dyskinesia)

Example 12. Simulated Pharmacokinetic Characteristics of Amantadine ERFormulations with a Delayed Release Coat Suitable for Night TimeAdministration

Objective: The objective is to evaluate the pharmacokinetic profile oftwo alternative ER formulations of amantadine suitable for nighttimeadministration—Formulation 1, which is the formulation tested in Example7, and Formulation 2, which is the formulation tested in Example 7, butwith a delayed release over coat on top of the extended release coat.

Plasma concentration-time profiles from healthy volunteers, who receivedmultiple doses of the ER and IR formulations of amantadine per studyprocedures described in Example 7 (ADS-5101-MD-104), were used todevelop a pharmacokinetic model describing each of the two formulations.This study was an open-label, randomized, two-treatment, two-period,two-way crossover study comparing once-daily amantadine ER capsules andtwice-daily amantadine IR tablets in 26 healthy, adult male and femalevolunteers. Complete data from 24 individuals were used in thisexercise. Blood samples for pharmacokinetic evaluation were collectedafter single dosing on Day 1 and at steady state on Day 9. In the firststep of the analysis, WinNonlin 5.2.1 (Pharsight Corp., Mountain View,Calif.) was used to fit a one-compartment model with first-order inputand first-order output, weighted 1/y (where y is the amantadine plasmaconcentration), to each individual's plasma concentration-time dataobtained after single (Day 1) and repeated (Day 9) dose administrationof amantadine IR and ER; the fitting was done separately for bothformulations, but simultaneously for both days. Modeling assumptionsemployed include dose proportionality and constant clearance as afunction of time.

The model is described by the following equation

$\begin{matrix}{C = {\frac{FD}{V( {k_{a} - k} )}\lbrack {{\exp ( {- {k( {t - t_{{lag})}} )}} )} - {\exp ( {- {k_{a}( {t - t_{{lag})}} )}} )}} \rbrack}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

where C is the plasma concentration, F is the absolute bioavailability,D is dose, V is the volume of distribution, k_(a) is the absorption rateconstant, k is the elimination rate constant, t is time, and t_(lag) isthe lag time of absorption. The goodness of fit was verified bycomparing the individual model predicted and observed concentration-timedata from Study ADS-5101-MD-104. After Equation 1 was fitted to eachindividual's plasma concentration-time data, model parameter estimatesof V/F, k_(a), k, and t_(lag) were obtained for each of the 24 subjects.The goodness of the prediction at steady state was confirmed bycomparing the observed data and predicted steady-state concentrations ofamantadine obtained after daily dosing of 200 mg as the ER and IRformulations (Day 9).

In the second step of the analysis, individual model parameter estimateswere used to simulate steady-state concentration-time profiles for eachindividual for both formulations by reinserting the individual parameterestimates into Equation 1, and summing the contribution of 7 sequentialdays of dosing, according to the following dosing regimens:

-   -   1. Once Daily (QD) dosing of 200 mg of the ER Formulation 1 to        steady state    -   2. Once Daily (QD) dosing of 200 mg of the ER Formulation 2 to        steady state

Results: FIG. 7 shows the simulated steady state plasma concentrationtime profiles for the two ER amantadine formulations. (Amantadine bloodplasma concentrations are shown on the y, time of day on the x-axis.) Asshown in FIG. 7, the ER amantadine formulation 2 administered once dailyat night results in about a 4 hour delay in achieving peak plasmaconcentration at steady state relative to formulation 1. Thus, aformulation comprising a delayed release coat on top of the extendedrelease coat has a very favorable pharmacokinetic profile in that itmaximizes the daytime plasma exposure to amantadine whilst minimizingnight plasma exposure at steady state.

While preferred embodiments of the present invention have been shown anddescribed herein, such embodiments are provided by way of example only.Numerous variations, changes, and substitutions will now occur to thoseskilled in the art without departing from the invention. It should beunderstood that various alternatives to the embodiments of the inventiondescribed herein may be employed in practicing the invention. Allreferences cited herein are incorporated herein by reference in theirentirety.

What is claimed is: 1.-28. (canceled)
 29. A method administering a doseof a pharmaceutical composition of a drug selected from the groupconsisting of amantadine and pharmaceutically acceptable salts thereofto a human patient, comprising administering said dose of saidpharmaceutical composition to said human patient orally, once daily 0 to4 hours before bedtime, wherein said dose of said pharmaceuticalcomposition consists of: (i) 220 mg to 445 mg of a drug selected fromthe group consisting of amantadine and pharmaceutically acceptable saltsthereof; and (ii) one or more excipients, wherein at least one of saidone or more excipients modifies the release of said drug to provide anextended release form, and wherein when said pharmaceutical compositionis dosed in a single dose, fasted, human pharmacokinetic study inhealthy subjects, the fractional AUC₀₋₄ for amantadine is less than 5%of AUC_(0-inf) for amantadine and the Tmax of amantadine is 8 to 18hours.
 30. A method administering a dose of a pharmaceutical compositionof a drug selected from the group consisting of amantadine andpharmaceutically acceptable salts thereof to a human patient, comprisingadministering said dose of said pharmaceutical composition to said humanpatient orally, once daily 0 to 4 hours before bedtime, wherein saiddose of said pharmaceutical composition consists of: (i) 220 mg to 445mg of a drug selected from the group consisting of amantadine andpharmaceutically acceptable salts thereof; and (ii) one or moreexcipients, wherein at least one of said one or more excipients modifiesthe release of said drug to provide an extended release form, andwherein when said pharmaceutical composition is tested in a single dose,fasted, human pharmacokinetic study in healthy subjects, the fractionalAUC₀₋₈ for amantadine in a subject of said study is 5% to 15% ofAUC_(0-inf) for said subject and the Tmax for amantadine in a subject ofsaid study is 8 to 18 hours.
 31. A method administering a dose of apharmaceutical composition of a drug selected from the group consistingof amantadine and pharmaceutically acceptable salts thereof to a humanpatient, comprising administering said dose of said pharmaceuticalcomposition to said human patient orally, once daily 0 to 4 hours beforebedtime, wherein said dose of said pharmaceutical composition consistsof: (i) 220 mg to 445 mg of a drug selected from the group consisting ofamantadine and pharmaceutically acceptable salts thereof; and (ii) oneor more excipients, wherein at least one of said one or more excipientsmodifies the release of said drug to provide an extended release form,and wherein when said pharmaceutical composition is tested in a singledose, fasted, human pharmacokinetic study in healthy subjects, thefractional AUC₀₋₄ for amantadine in a subject of said study is less than5% of AUC_(0-inf) for said subject and the Cmax for amantadine in asubject of said study is 1.0 to 2.8 ng/ml per mg of amantadine.
 32. Amethod administering a dose of a pharmaceutical composition of a drugselected from the group consisting of amantadine and pharmaceuticallyacceptable salts thereof to a human patient, comprising administeringsaid dose of said pharmaceutical composition to said human patientorally, once daily 0 to 4 hours before bedtime, wherein said dose ofsaid pharmaceutical composition consists of: (i) 220 mg to 445 mg of adrug selected from the group consisting of amantadine andpharmaceutically acceptable salts thereof; and (ii) one or moreexcipients, wherein at least one of said one or more excipients modifiesthe release of said drug to provide an extended release form, andwherein when said pharmaceutical composition is tested in a single dose,fasted, human pharmacokinetic study in healthy subjects, the fractionalAUC₀₋₈ for amantadine in a subject of said study is 5% to 15% ofAUC_(0-inf) for said subject and the Cmax for amantadine in a subject ofsaid study is 1.0 to 2.8 ng/ml per mg of amantadine.
 33. The method ofclaim 29, wherein when said pharmaceutical composition is dosed in asingle dose, fasted, human pharmacokinetic study in healthy subjects,the Cmax for amantadine in a subject of said study is 1.0 to 2.8 ng/mlper mg of amantadine.
 34. The method of claim 29, wherein when saidpharmaceutical composition is tested in a single dose, fasted, humanpharmacokinetic study in healthy subjects, the AUC_(0-inf) foramantadine in a subject of said study is 40 to 75 ng*h/ml per mg ofamantadine.
 35. The method of claim 33, wherein when said pharmaceuticalcomposition is tested in a single dose, fasted, human pharmacokineticstudy in healthy subjects, the AUC_(0-inf) for amantadine in a subjectof said study is 40 to 75 ng*h/ml per mg of amantadine.
 36. The methodof claim 29, wherein when said pharmaceutical composition is tested in amultiple dose, fasted, human pharmacokinetic study in healthyindividuals, the steady state AUC₀₋₂₄ for amantadine in an individual ofsaid study is 44 to 83 ng*h/ml per mg of amantadine.
 37. The method ofclaim 33, wherein when said pharmaceutical composition is tested in amultiple dose, fasted, human pharmacokinetic study in healthyindividuals, the steady state AUC₀₋₂₄ for amantadine in an individual ofsaid study is 44 to 83 ng*h/ml per mg of amantadine.
 38. The method ofclaim 29, wherein said patient is being treated for Parkinson's disease.39. The method of claim 33, wherein said patient is being treated forParkinson's disease.
 40. The method of claim 36, wherein said patient isbeing treated for Parkinson's disease.
 41. The method of claim 38,wherein said patient suffers from levodopa induced dyskinesia.
 42. Themethod of claim 41, wherein the method reduces the frequency or severityof levodopa induced dyskinesia.
 43. The method of claim 29, wherein saiddose of said pharmaceutical composition is encapsulated in 1 or 2 unitdosage forms.
 44. The method of claim 29, wherein said dose of saidpharmaceutical composition is encapsulated in one or two capsules. 46.The method of claim 30, wherein when said pharmaceutical composition isdosed in a single dose, fasted, human pharmacokinetic study in healthysubjects, the Cmax for amantadine in a subject of said study is 1.0 to2.8 ng/ml per mg of amantadine.
 47. The method of claim 30, wherein whensaid pharmaceutical composition is tested in a single dose, fasted,human pharmacokinetic study in healthy subjects, the AUC_(0-inf) foramantadine in a subject of said study is 40 to 75 ng*h/ml per mg ofamantadine.
 48. The method of claim 46, wherein when said pharmaceuticalcomposition is tested in a single dose, fasted, human pharmacokineticstudy in healthy subjects, the AUC_(0-inf) for amantadine in a subjectof said study is 40 to 75 ng*h/ml per mg of amantadine.
 49. The methodof claim 30, wherein when said pharmaceutical composition is tested in amultiple dose, fasted, human pharmacokinetic study in healthyindividuals, the steady state AUC₀₋₂₄ for amantadine in an individual ofsaid study is 44 to 83 ng*h/ml per mg of amantadine.
 50. The method ofclaim 46, wherein when said pharmaceutical composition is tested in amultiple dose, fasted, human pharmacokinetic study in healthyindividuals, the steady state AUC₀₋₂₄ for amantadine in an individual ofsaid study is 44 to 83 ng*h/ml per mg of amantadine.
 51. The method ofclaim 30, wherein said patient is being treated for Parkinson's disease.52. The method of claim 46, wherein said patient is being treated forParkinson's disease.
 53. The method of claim 49, wherein said patient isbeing treated for Parkinson's disease.
 54. The method of claim 51,wherein said patient suffers from levodopa induced dyskinesia.
 55. Themethod of claim 54, wherein the method reduces the frequency or severityof levodopa induced dyskinesia.
 56. The method of claim 30, wherein saiddose of said pharmaceutical composition is encapsulated in 1 or 2 unitdosage forms.
 57. The method of claim 30, wherein said dose of saidpharmaceutical composition is encapsulated in one or two capsules. 58.The method of claim 31, wherein when said pharmaceutical composition istested in a single dose, fasted, human pharmacokinetic study in healthysubjects, the AUC_(0-inf) for amantadine in a subject of said study is40 to 75 ng*h/ml per mg of amantadine.
 59. The method of claim 31,wherein when said pharmaceutical composition is tested in a multipledose, fasted, human pharmacokinetic study in healthy individuals, thesteady state AUC₀₋₂₄ for amantadine in an individual of said study is 44to 83 ng*h/ml per mg of amantadine.
 60. The method of claim 31, whereinsaid patient is being treated for Parkinson's disease.
 61. The method ofclaim 59, wherein said patient is being treated for Parkinson's disease.62. The method of claim 60, wherein said patient suffers from levodopainduced dyskinesia.
 63. The method of claim 62, wherein the methodreduces the frequency or severity of levodopa induced dyskinesia. 64.The method of claim 31, wherein said dose of said pharmaceuticalcomposition is encapsulated in 1 or 2 unit dosage forms.
 65. The methodof claim 31, wherein said dose of said pharmaceutical composition isencapsulated in one or two capsules.
 66. The method of claim 32, whereinwhen said pharmaceutical composition is tested in a single dose, fasted,human pharmacokinetic study in healthy subjects, the AUC_(0-inf) foramantadine in a subject of said study is 40 to 75 ng*h/ml per mg ofamantadine.
 67. The method of claim 32, wherein when said pharmaceuticalcomposition is tested in a multiple dose, fasted, human pharmacokineticstudy in healthy individuals, the steady state AUC₀₋₂₄ for amantadine inan individual of said study is 44 to 83 ng*h/ml per mg of amantadine.68. The method of claim 32, wherein said patient is being treated forParkinson's disease.
 69. The method of claim 67, wherein said patient isbeing treated for Parkinson's disease.
 70. The method of claim 68,wherein said patient suffers from levodopa induced dyskinesia.
 71. Themethod of claim 70, wherein the method reduces the frequency or severityof levodopa induced dyskinesia.
 72. The method of claim 32, wherein saiddose of said pharmaceutical composition is encapsulated in 1 or 2 unitdosage forms.
 73. The method of claim 32, wherein said dose of saidpharmaceutical composition is encapsulated in one or two capsules.